WO2005026175A1 - Thienopyrazoles - Google Patents

Thienopyrazoles Download PDF

Info

Publication number
WO2005026175A1
WO2005026175A1 PCT/US2004/023814 US2004023814W WO2005026175A1 WO 2005026175 A1 WO2005026175 A1 WO 2005026175A1 US 2004023814 W US2004023814 W US 2004023814W WO 2005026175 A1 WO2005026175 A1 WO 2005026175A1
Authority
WO
WIPO (PCT)
Prior art keywords
thieno
pyrazol
indol
optionally substituted
piperidin
Prior art date
Application number
PCT/US2004/023814
Other languages
English (en)
Inventor
John Gerard Jurcak
Matthieu Barrague
Timothy Alan Gillespy
Michael Louis Edwards
Kwon Yon Musick
Philip Marvin Weintraub
Yan Du
Ramalinga M. Dharanipragada
Ashfaq Ahmed Parkar
Original Assignee
Aventis Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA06001827A priority Critical patent/MXPA06001827A/es
Priority to EP04779049A priority patent/EP1682553B1/fr
Application filed by Aventis Pharmaceuticals Inc. filed Critical Aventis Pharmaceuticals Inc.
Priority to DE602004027288T priority patent/DE602004027288D1/de
Priority to AU2004272507A priority patent/AU2004272507B2/en
Priority to SI200431462T priority patent/SI1682553T1/sl
Priority to YUP-2006/0162A priority patent/RS20060162A/sr
Priority to JP2006525328A priority patent/JP4879739B2/ja
Priority to CA2538032A priority patent/CA2538032C/fr
Priority to PL04779049T priority patent/PL1682553T3/pl
Priority to DK04779049.8T priority patent/DK1682553T3/da
Priority to NZ545421A priority patent/NZ545421A/en
Priority to AT04779049T priority patent/ATE468341T1/de
Priority to MEP-209/08A priority patent/MEP20908A/xx
Priority to BRPI0414215-2A priority patent/BRPI0414215A/pt
Publication of WO2005026175A1 publication Critical patent/WO2005026175A1/fr
Priority to TNP2006000058A priority patent/TNSN06058A1/en
Priority to IL173916A priority patent/IL173916A/en
Priority to US11/368,566 priority patent/US7518000B2/en
Priority to NO20061626A priority patent/NO20061626L/no
Priority to HK07100592A priority patent/HK1095587A1/xx
Priority to US12/411,818 priority patent/US7928231B2/en
Priority to HR20100398T priority patent/HRP20100398T1/hr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is directed to thienopyrazoles of Formula I, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition ofthe protein kinases, in particular interleukin-2 inducible tyrosine kinase (ITK).
  • ITK interleukin-2 inducible tyrosine kinase
  • Protein kinases are a family of enzymes that participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into several groups; those which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues and those which preferentially catalyse the phosphorylation of hydroxy groups of tyrosine residues [S.K.Hanks and T.Hunter, FASEB. J., 1995, 9, pages 576-596]. Such phosphorylations may greatly modify the function ofthe proteins; thus, protein kinases play an important role in regulating a wide variety of cell processes including, especially, metabolism, cell proliferation, cell differentiation or cell survival.
  • ITK is a T cell specific tyrosine kinase of the Tec family that is required for normal Th2 function. Asthma is a disease characterised by increased Th2 cytokine production including IL-4. An inhibitor of ITK should therefore have an impact on disease progression in asthma through inhibition of Th2 cytokine production.
  • thienopyrazoles which have valuable pharmaceutical properties, in particular, the ability to inhibit protein kinases, more particularly, the ability to inhibit the protein kinase ITK.
  • the invention is directed to compounds of Formula I,
  • X is N, or C-R 7 ;
  • Xi is N. or C-R 1 ;
  • Preferred compounds ofthe present invention are those of Formula I wherein X is N.
  • a particular group of compounds ofthe invention axe compounds of Formula (la)
  • R4 5 R5 and R ⁇ are as hereinbefore defined.
  • Nomenclature The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein
  • R2 is hydrogen
  • R ⁇ is 3-(4-hydroxy-piperidin-l-yl)-propyloxy (HO — N-(CH ) 3 -o-
  • R4 is hydrogen, R is dimethylaminomethyl ( N — CH . -) and R is hydrogen; that is, a H-C compound having the following structure:
  • Example 15 l- ⁇ 3-[2-(l H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-5-yloxy] -propyl ⁇ -piperidin-4-ol, Example 16; l- ⁇ 3-[2-(l H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-5-yloxy] -propyl ⁇ -piperidin-3 -ol, Example 17;
  • Example 51 cyclohexylmethyl- [2-( 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-5 -ylmethyl] -amine, Example 52;
  • Example 62 1 - ⁇ 3 - [6-(3-piperidin- 1 -yl-propoxy)- 1 H-indol-2-yl] - 1 H-thieno [3 ,2-c]pyrazol-5 -ylmethyl ⁇ - piperidin-4-ol, Example 63;
  • Example 64 methyl- ⁇ 3 -[6-(3 -piperidin- 1 -yl-propoxy)- 1 H-indol-2-yl] - 1 H-thieno [3 ,2-c]pyrazol-5-ylmethyl ⁇ - pyridin-2-yl-amine, Example 65; benzyl- ⁇ 3 - [6-(3 -piperidin- 1 -yl-propoxy)- 1 H-indol-2-yl] - 1 H-thieno [3 ,2-c]pyrazol-5-yhnethyl ⁇ - amine, Example 66;
  • Example 72 l- ⁇ 3-[6-(l -ethyl- 1 -hydroxy-propyl)- 1 H-indol-2-yl] - 1 H-thieno [3 ,2-c]pyrazol-5-ylmethyl ⁇ - ⁇ iperidin-4-ol, Example 73;
  • Example 98 3-ol, Example 98; and prodrugs, acid bioisosteres, pharmaceutically acceptable salts or solvates of such compounds or prodrugs, and acid bioisosteres of such salts or solvates.
  • the properties of these particular compounds are summarized in Table 1 below.
  • Figure 1 is chemical synthetic scheme depicting the process of making a compound of the present invention.
  • Patient includes both human and other mammals.
  • “Pharmaceutically effective amount” is meant to describe an amount of compound, composition, medicament or other active ingredient effective in producing the desired therapeutic effect.
  • Acid bioisostere means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283 "Bioisosterism In Drag Design”; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design”; Zhao, Huaxue Tongbao, 1995, pages 34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drag Design”; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Desigmab initio Electronic Distributions In Bioisosteres”).
  • 3,5-dioxo-l,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3 -hydoxy- 1 -methylpyrazolyl.
  • acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as described o p herein.
  • exemplary acyl groups include CH 3 — c- and CH 3 CH 2 — c- .
  • Optionally substituted acyl means an acyl group which may be substituted on the alkyl portion by one or more alkyl group o substituents.
  • exemplary substituted acyl groups include CF — c- .
  • acylamino is an acyl-NH- group wherein acyl is as defined herein.
  • Optionally substituted acylamino means an acylamino group which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • Alkenyl means an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
  • "Optionally substituted alkenyl” means an alkenyl group which may be substituted by one or more alkyl group substituents.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as described herein.
  • Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • Optionally substituted alkoxy means an alkoxy group which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • Exemplary substituted alkoxy groups include H 3 C-N-(CH 2 ) ⁇ - O- .
  • CH 3 CH 2 CH 3 CH j CHK-H
  • Alkoxyalkyl means an alkyl-O-alkyl- group in which the alkyl group is as described herein.
  • exemplary alkoxymethyl groups include methoxymethyl and ethoxymethyl.
  • Optionally substituted alkoxyalkyl means an alkoxyalkyl which may be substituted on the alkyl portions by one or more alkyl group substituents.
  • Alkoxycarbonyl means an alkyl-O-CO- group in which the alkyl group is as described herein.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Optionally substituted alkoxycarbonyl means an alkoxycarbonyl which may be substituted on the alkyl portions by one or more alkyl group substituents.
  • Alkyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain. Particular alkyl groups have from 1 to about 6 carbon atoms. Exemplary alkyl groups include C ⁇ _galkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl.
  • Optionally substituted alkyl means an alkyl group which may be substituted by one or more alkyl group substituents, where "alkyl group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, optionally substituted aroyl, optionally substituted aroylamino, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkyloxycarbonyl, optionally substituted arylalkylthio, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted arylthio, carboxy, cyano, cycloalkenyl,
  • CH 3 CH-CH- CH 3 CH- substituted alkyl groups include HO-CH-- ,H 3 C-CH- , CH J CH J -C- , CH ⁇ H J -C- , (CH 3 ) 2 CH-C- . OH OH OH OH OH
  • Alkylene means a straight or branched bivalent hydrocarbon chain having from 1 to about 15 carbon atoms. Particular alkylene groups are the lower alkylene groups having from 1 to about 6 carbon atoms. Exemplary groups include methylene and ethylene.
  • Alkylsulfinyl means an alkyl-SO- group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is C ⁇ _6alkyl.
  • Optionally substituted alkylsulfinyl means an alkylsulfinyl which may be substituted on the alkyl portion with one or more alkyl group substituents.
  • Alkylsulfonyl means an alkyl-SO 2 - group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is C ⁇ _6alkyl.
  • Optionally substituted alkylsulfonyl means an alkylsulfonyl which may be substituted on the alkyl portion with one or more alkyl group substituents.
  • Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C ⁇ _6_ ⁇ lkyl.
  • Optionally substituted alkylsulfonylcarbamoyl means an alkylsulfonylcarbamoyl group which may be substituted on the alkyl portion with one or more alkyl group substituents.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
  • Optionally substituted alkylthio means an alkylthio group which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl. "Optionally substituted alkynyl” means an alkynyl group which may be substituted with one or more alkyl group substituents.
  • Aroyl means an aryl-CO- group in which the aryl group is as described herein. Exemplary groups include benzoyl and 1- and 2-naphthoyl. "Optionally substituted aroyl” means an aroyl group, the aryl portion of which may be substituted by one or more aryl group substituents as defined herein.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as previously defined.
  • Optionally substituted aroylamino means an aroylamino group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Aryl as a group or part of a group denotes: (i) a monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring.
  • aryl group substituents which may be the same or different, where "aryl group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyl, arylalkyloxy, arylalkyloxycarbonyl, aiylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkylalkyl,
  • Optionally substituted benzene ring means a benzene ring which may be substituted by one or more aryl group substituents.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci.galkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemefhyl. "Optionally substituted arylalkyl” means an arylalkyl group which may be substituted on the aryl portion by one or more aryl group substituents, and which may be substituted on the alkyl portion by one or more alkyl group substituents. Exemplary substituted arylalkyl groups include (/ / X — CH- and OH
  • Arylalkyloxy means an arylalkyl-O- group in which the arylalkyl group is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. "Optionally substituted arylalkyloxy” means an arylalkyloxy group which may be substituted on the aryl portion by one or more aryl group substituents, and on the alkyl portion by one or more alkyl group substituents.
  • Arylalkyloxyalkyl means an arylalkyl-O-alkyl- group in which the arylalkyl and alkyl groups are as previously described. Exemplary arylalkyloxyalkyl groups include benzyloxymethyl and 1- or 2-naphthalenemethoxymethyl.
  • Optionally substituted arylalkyloxyalkyl means an arylalkyloxyalkyl group which may be substituted on the aryl portion by one or more aryl group substituents, and on the alkyl portions by one or more alkyl group substituents.
  • Arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
  • Optionally substituted arylalkyloxycarbonyl means an arylalkyloxycarbonyl group which may be substituted on the aryl portion by one or more aryl group substituents, and on the alkyl portion by one or more alkyl group substituents.
  • Aryloxyalkyl means an aryl-O-alkyl group.
  • An exemplary aryloxyalkyl group is phenoxymethyl.
  • Optionally substituted aryloxyalkyl is an aryloxyalkyl group which may be substituted on the aryl portion by one or more aryl group substituents, and on the alkyl portion by one or more alkyl group substituents.
  • Arylalkylthio means an arylalkyl-S- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkylthio group is benzylthio.
  • Optionally substituted arylalkylthio is an arylalkylthio group which may be substituted on the aryl portion by one or more aryl group substituents, and on the alkyl portion by one or more alkyl group substituents.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy. "Optionally substituted aryloxy” means an aryloxy group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Aryloxycarbonyl means an aryl-O-CO- group in which the aryl group is as previously described.
  • exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • Optionally substituted aryloxycarbonyl means an aryloxycarbonyl group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Arylsulfinyl means an aryl-SO- group in which the aryl group is as previously described.
  • Optionally substituted arylsulfinyl means an arylsulfinyl group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Arylsulfonyl means an aryl-SO 2 - group in which the aryl group is as previously described.
  • Optionally substituted arylsulfonyl means an arylsulfinyl group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Optionally substituted arylsulfonylcarbamoyl means an arylsulfonylcarbamoyl group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • Exemplary arylthio groups include phenylthio and naphthylthio.
  • Optionally substituted arylthio means an arylthio group which may be substituted on the aryl portion by one or more aryl group substituents.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 5 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Exemplary multicyclic cycloalkenyl ring include norbornenyl.
  • Optionally substituted cycloalkenyl means a cycloalkenyl group which may be substituted by one or more alkyl group substituents.
  • Cycloalkoxyalkyl means a cycloalkyl-O-alkyl-group in which the cycloalkyl group is as described hereinafter.
  • Exemplary cycloalkoxyalkyl groups include cyclopropyloxymethyl and cyclopentyloxymethyl.
  • Optionally substituted cycloalkoxyalkyl means a cycloalkoxyalkyl group which may be substituted by one or more alkyl group substituents.
  • Cycloalkyl means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Exemplary multicyclic cycloalkyl rings include perhydronaphthyl, adamant-(l- or 2-)yl and norbornyl and spirocyclic groups e.g. spiro[4,4]non-2yl.
  • "Optionally substituted cycloalkyl” means a cycloalkyl group which may be substituted by alkyl or one or more alkyl group substituents.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptyhnethyl.
  • Optionally substituted cycloalkylalkyl means a cycloalkylalkyl group which may be substituted by alkyl or one or more alkyl group substituents.
  • Cycloalkyloxy means a cycloalkyl-O- group in which the cycloalkyl group is as described herein.
  • Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
  • Optionally substituted cycloalkyloxy means a cycloalkyloxy group which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • Heteroaroyl means a heteroaryl-CO- group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
  • Optionally substituted heteroaroyl means a heteroaroyl group which may be substituted with one or more aryl group substituents.
  • Heteroaroylamino means a heteroaroyl-NH- group in which the heteroaroyl moiety is as previously described.
  • Optionally substituted heteroaroylamino means a heteroaroylamino group which may be substituted with one or more aryl group substituents.
  • Heteroaryl as a group or part of a group denotes an aromatic monocyclic or multicyclic organic moiety of about 5 to about 14 ring members in which one or more ofthe ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • heteroaryl groups examples include benzimidazolyl, firryl, imidazolyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups.
  • "Optionally substituted heteroaryl” means a heteroaryl group which may be substituted by one or more aryl group substituents.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C ⁇ _4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. "Optionally substituted heteroarylalkyl” means a heteroarylalkyl group which may be substituted on the heteroaryl portion by one or more aryl group substituents, and which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • Heteroarylalkoxy means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described.
  • Exemplary heteroaryloxy groups include pyridylmethoxy.
  • Optionally substituted heteroarylalkoxy means a heteroarylalkoxy group which may be substituted on the heteroaryl portion by one or more aryl group substituents, and which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • Heteroarylalkyloxyalkyl means a heteroarylalkyl-O-alkyl- group in which the heteroarylalkyl and alkyl groups are as previously described.
  • heteroarylalkyloxyalkyl groups include 4-pyridylmethoxymethyl and 3- or 4-quinolinemethoxymethyl.
  • Optionally substituted heteroarylalkyloxyalkyl means a heteroarylalkyloxyalkyl group which may be substituted on the heteroaryl portion by one or more aryl group substituents, and on the alkyl portions by one or more alkyl group substituents.
  • Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • Optionally substituted heteroaryloxy means a heteroaryloxy group which may be substituted on the heteroaryl portion by one or more aryl group substituents.
  • Heteroaryloxyalkyl means a heteroaryl-O-alkyl group in which heteroaryl and alkyl are as described herein.
  • Optionally substituted heteroaryloxyalkyl means a heteroaryloxyalkyl group which may be substituted on the heteroaryl portion by one or more aryl group substituents, and on the alkyl portion by one ore more alkyl group substituents.
  • Optionally substituted heteroaiylsulfonylcarbamoyl means a heteroaiylsulfonylcarbamoyl group which may be substituted with one or more aryl group substituents.
  • Heterocycloalkyl means a non-aromatic or partially aromatic monocyclic or multicyclic organic moiety of about 5 to about 14 ring members which contains one or more heteroatoms selected from O, S or N ⁇ 9, where Y ⁇ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, cycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
  • exemplary heterocycloalkyl groups include morpholine, piperidine, piperazine, pyrrolidine, tetrahydrofuran and perhydropyran.
  • Optionally substituted heterocycloalkyl means a heterocycloalkyl group which may be substituted by alkyl or by one or more alkyl group substituents.
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • Optionally substituted heterocycloalkylalkyl means a heterocycloalkylalkyl group which may be substituted by alkyl or one or more alkyl group substituents.
  • Heterocycloalkyloxy means a heterocycloalkyl-O- group in which heterocycloalkyl is as previously defined.
  • Optionally substituted heterocycloalkyloxy means a heterocycloalkyloxy group which may be substituted on the heterocycloalkyloxy portion by alkyl or by one or more alkyl group substituents.
  • Heterocycloalkyloxyalkyl means a heterocycloalkyl-O-alkyl group in which heterocycloalkyl is as previously defined.
  • Optionally substituted heterocycloalkyloxyalkyl means a heterocycloalkyloxyalkyl group which may be substituted on the heterocycloalkyloxy portion or the alkyl portion by one or more alkyl group substituents.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl groups contain C ⁇ _4alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Optionally substituted hydroxyalkyl” means a hydroxyalkyl group which may be substituted on the alkyl portion by one or more alkyl group substituents.
  • ⁇ ⁇ 8 N- means a substituted or unsubstituted amino group, wherein Y? and Y 8 are as previously described.
  • exemplary groups include amino (H 2 N-), memylamino, ethylmemylamino, dime ylamino and die ylamino.
  • ⁇ ⁇ 8 NCO- means a substituted or unsubstituted carbamoyl group, wherein Y ⁇ and Y 8 are as previously described. Exemplary groups are carbamoyl (H 2 NCO-) and dimethylcarbamoyl (Me NCO-).
  • ⁇ 7 ⁇ 8 NSO 2 - means a substituted or unsubstituted sulfamoyl group, wherein Y? and
  • Y 8 are as previously described.
  • Exemplary groups are sulfamoyl (H NSO 2 -) and dimethylsulfamoyl (Me 2 NSO 2 -).
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I, including N-oxides thereof.
  • an ester of a compound of Formula I containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • an ester of a compound of Formula I containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice ofthe crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • Suitable esters of compounds of Formula I containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methyle ⁇ e-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • Suitable esters of compounds of Formula I containing a carboxy group are for example those described by F.J.Leinweber, Drug Metab. Res., 1987, 18, page 379.
  • esters of compounds of Formula I containing a hydroxy group may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32_, page 2503-2507, and include substituted (an ⁇ nomethyl)-benzoates, for example diall ⁇ ylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholmomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin- 1 -yl)benzoates.
  • substituted (an ⁇ nomethyl)-benzoates for example diall ⁇ ylamino-methylbenzoates in which the two alkyl groups may be
  • Some ofthe compounds ofthe present invention are basic, and such compounds are useful in the form ofthe free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acid addition salts are a more convenient form for use; and in practice, use ofthe salt form inherently amounts to use ofthe free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses ofthe salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions.
  • compositions are preferred, all acid addition salts are useful as sources ofthe free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • Pharmaceutically acceptable salts within the scope ofthe invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g.
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use ofthe salt form inherently amounts to use ofthe free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses ofthe salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations.
  • Pharmaceutically acceptable salts including those derived from alkali and alkaline earth metal salts, within the scope ofthe invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminiixm hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, e ylenediamine, N-memyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, s(hyckoxymemyl)aminomethane, tetramethylammonium hydroxide, and the like.
  • salts of compounds ofthe invention are useful for the purposes of purification ofthe compounds, for example by exploitation ofthe solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • the compounds ofthe invention are ITK inhibitors and therefore have useful pharmacological activity. Accordingly, they are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders.
  • the present invention thus provides, according to a further aspect, compounds ofthe invention and compositions containing compounds ofthe invention for use in therapy.
  • the present invention provides compounds ofthe invention and compositions containing compounds ofthe invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of ITK.
  • compounds ofthe present invention are useful in the treatment of asthma.
  • references herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
  • the present invention also includes within its scope pharmaceutical compositions comprising at least one ofthe compounds ofthe invention in association with a pharmaceutically acceptable carrier or excipient.
  • Compounds ofthe invention may be administered by any suitable means.
  • compounds ofthe present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
  • compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • the compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • emulsions, suspensions or solutions ofthe products according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions ofthe pharmaceutically acceptable salts, are used.
  • vegetable oil for example sesame oil, groundnut oil or olive oil
  • aqueous-organic solutions such as water and propylene glycol
  • injectable organic esters such as ethyl oleate
  • sterile aqueous solutions ofthe pharmaceutically acceptable salts are used.
  • the solutions ofthe salts ofthe products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • aqueous solutions also comprising solutions ofthe salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration.
  • gels water or alcohol based
  • creams or ointments containing compounds ofthe invention may be used.
  • Compounds ofthe invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
  • inhalation compounds ofthe invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound ofthe invention.
  • the percentage of active ingredient in the compositions ofthe invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time.
  • the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of adn ⁇ iistration and the duration ofthe treatment, and the condition ofthe patient.
  • the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration.
  • the doses will be deteraiined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy ofthe medicinal product.
  • the compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect.
  • the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
  • compounds ofthe present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds ofthe invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of Formula I hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates. Additionally, in situations where tautomers ofthe compounds of Formula I are possible, the present invention is intended to include all tautomeric forms ofthe compounds.
  • acid addition salts ofthe compounds of this invention may be prepared by reaction ofthe free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts ofthe compounds of this invention may be prepared either by dissolving the free base in water or an aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, such as tetrahydrofuran, in which case the salt separates directly or can be obtained by concentration ofthe solution.
  • parent compounds of the invention can be regenerated from their acid addition salts by the application or adaptation of known methods.
  • parent compounds ofthe invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • base addition salts ofthe compounds of this invention may be prepared by reaction ofthe free acid with the appropriate base, by the application or adaptation of known methods.
  • the base addition salts ofthe compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration ofthe solution.
  • parent compounds of the invention can be regenerated from their base addition salts by the application or adaptation of known methods.
  • parent compounds ofthe invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • Hydrates of compounds ofthe present invention may be conveniently prepared by recrystallisation from water.
  • the starting materials and intermediates which are not commercially available may be prepared by the application or adaptation of known methods, for example methods as described in the Examples or their obvious chemical equivalents.
  • the present invention is further exemplified but not limited by the following illustrative Examples.
  • HN( ⁇ 3)( ⁇ 4) i optionally substituted heterocycloalkyl-H, where heterocycloalkyl-H indicates a hydrogen on a saturated nitrogen within the heterocycloalkyl ring, or Y 3 and ⁇ 4 are Y ⁇ and Y 8 , respectively, or protected derivatives thereof, or intermediate groups thereto.
  • the 2-(l H-thieno [3 ,2-c]pyrazol-3-yl)-lH-indoles ofthe present invention of formula (la), in which one of Rl, R 2 , R3 and R4 is an optionally substituted alkyl group of formula R— CH- [where R a is alkyl, cycloalkyl, optionally substituted aryl or heteroaryl] and the others OH are hydrogen, are generally prepared as shown in Scheme V.
  • R— c- [where R a and R D are optionally substituted alkyl, optionally substituted cycloalkyl, OH optionally substituted aryl or optionally substituted heteroaryl] and the others are hydrogen, are generally prepared as shown in Scheme VI.
  • R— c- examples include c ⁇ CH j -c- , CH j CH j -c- , (CH 3 ) 2 CH-C- .
  • Compounds ofthe invention may also be prepared by interconversion of other compounds ofthe invention.
  • compounds of formula (I) containing a carboxy group may be prepared by hydrolysis ofthe corresponding esters.
  • the hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux.
  • a base such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate
  • organic solvents such as dioxan, tetrahydrofuran or methanol
  • the hydrolysis ofthe esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • an inorganic acid such as hydrochloric acid
  • an aqueous/inert organic solvent mixture using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • compounds of formula (I) containing a carboxy group may be prepared by acid catalysed removal ofthe tert-butyl group ofthe corresponding tert-butyl esters using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
  • compounds of formula (I) containing a carboxy group may be prepared by hydrogenation ofthe corresponding benzyl esters.
  • the reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature.
  • a suitable metal catalyst e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • Examples include (i) coupling in the presence of O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature, (ii) coupling in the presence of a carbodiimide, for example dicyclohexylcarbodiimide in the presence of triethylamine, (iii) treatment with 1-hydroxybenzotriazole and a carbodiimide, such as l-(3-dimemylammopropyl)-3-emylcarbodiimide, in an inert solvent such as dimethylformamide and at a temperature at about room temperature.
  • a carbodiimide for example dicyclohexylcarbodiimide in the presence of triethylamine
  • 3-(5-hyckoxymemyl-lH-indol-2-yl)-lH-thieno[3,2-c]pyrazole-5-carboxylic acid (Example 37) may be reacted with l-(4-fluorophenyl)piperazine in the presence of l-ethyl-3-(3- dime ylaminopropyl)carbodiimide and 1-hydroxybenzotriazole to produce [4-(4-fluoro- phenyl)-piperazin- 1 -yl] - [3 -(5-hydroxymethyl- 1 H-indol-2-yl)- 1 H-thieno [3 ,2-c]pyrazol-5-yl]- methanone (Example 38).
  • Chiral separations are performed using a ChiralPak AD 20 ⁇ M column (250 x 20mmJD) using isocratic elution conditions with 80:20:0.1 mixture of heptane/eth-inol/diethylamine, total run time 30 minutes with a flow rate of 1.0 mL/minute and detection at 254nM.
  • Chiral resolution and fraction analyses are performed using a ChiralPak AD 10 ⁇ M column (250 x 4.6mmID) using isocratic elution conditions with 70:30:0.2 mixture of hept- e/ethano diethylamine, total run time 30 minutes with a flow rate of 1.0 mL/minute and detection at 254nM.
  • LC/MS analyses are performed using the following method: Agilent 1100 Series HPLC with a YMC CombiScreen Pro CI 8 5.5 ⁇ m 4.6 mm by 33 mm reverse phase column using gradient elution with a mixture of (A) acetonitrile/0.1% trifluoroacetic acid and (B) water/0.1% trifluoroacetic acid (5%A:95%B to 95%A:5%B over 5.1 minutes) with a 1.2 mL/minute flow rate; Agilent 1100 Series wellplate autosampler with 2 ⁇ L injection; Agilent 1100 Series diode array detector with 215, 254 and 320 nM wavelength detection; Hewlett Packard 1100 Series mass spectrometer with electrospray and positive ionisation.
  • R ⁇ dete ⁇ ninations are performed utilizing pre-coated thin layer chromatography plates with silica gel 60 F 254 .
  • Oxalyl chloride (0.601 mL, 6.99 mmol, 1.2 eq) is added to a mixture of 3- bromothiophene-2-carboxylic acid (1.20 g, 5.80 mmol), N,N-dimethylformamide (several drops, catalytic amount), and anhydrous dichloromethane (25 mL) at ambient temperature under nitrogen over 20 minutes. The reaction is stirred for 17 hours, purged with nitrogen, and concentrated under reduced pressure to afford a tan solid.
  • the crude 3-bromothiophene-2- carbonyl chloride is dissolved in dichloromethane (25 mL) and added dropwise, over 10 minutes, to a 0°C solution of N,O-dimethylhydroxylamine hydrochloride (843 mg, 8.64 mmol), diisopropylethylamine (2.50 mL, 14.3 mmol), and dichloromethane (25 mL).
  • the reaction is allowed to gradually warm to ambient temperature overnight.
  • the reaction is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Example 2A To an ambient solution of 5-methoxybenzoimidazole (6.18 g, 41.7 mmol) in dimethylformamide (60 mL) under nitrogen is added sodium hydride (1.84 g of 60% oil dispersion, 46.0 mmol) in two portions and the reaction stirred at ambient temperature. After 0.5 hour, a solution of benzyl chloromethylether (7.83 g, 50 mmol) in dimethylformamide (40 mL) is added dropwise over 15 minutes and the reaction stirred at ambient temperature overnight. The reaction mixture is poured into water (500 ml) and extracted three times with ethyl acetate (150 mL).
  • the beige powder is triturated in dichloromethane to provide 5-(3 -piperidin- 1 -yl-propoxy)-2-( 1 H-thieno [3 ,2-c]pyrazol-3 -yl)-indole [12 mg, 18 %,
  • Example 14 1 - ⁇ 3 - ⁇ 2- 1 H-Thieno [3.2-c]pyrazol-3 -yl)- 1 H-indol-6-yloxy] -propyl ⁇ -pyrrolidin-3 -ol
  • Example 16 1-13- [2-( 1 H-Thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-5-yloxyl -propyl -piperidin-4-ol
  • Example 17 1 - ⁇ 3 -[2-( 1 H-Thieno [3.2-c]pyrazol-3 -yl)- 1 H-indol-5-yloxy] -propyl ⁇ -piperidin-3 -ol
  • Example 22 1 - (3 - [2-(5 -Dimethylaminoethyl- 1 H-thieno [3.2-c]pyrazol-3 -yl)- 1 h-indol-6-yloxy] -propyl ⁇ - piperidin-4-ol
  • Step 1 A mixture of 5-(tert-butyl-dimethyl-silanyloxymethyl)-lH-indole-2-boronic acid 1 -carboxylic acid tert-butyl ester [3.82 g, 9.42 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No. WO 02/32861], 3-iodo- thieno [3 ,2-c]pyrazole-l -carboxylic acid tert-butyl ester [4.0 g, 11.
  • Step 2 A solution of 2-(l-tert-butoxycarbonyl-lH-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl- dirnethyl-silanyloxymethyl)-indole-l -carboxylic acid tert-butyl ester [3.8 g, 6.51 mmol, Intermediate (9)]) in anhydrous tetrahydrofuran (40 mL) is cooled to 0°C. To it is added tetrabutylammonium fluoride (1M in tetrahydrofuran, 10 mL) drop wise. Stirred at 0°C for 20 minutes then at room temperature for 20 minutes.
  • Step 3 To a solution of 2-(l-tert-butoxycarbonyl-lH-thieno[3,2-c]pyrazol-3-yl)-5- hydroxymethyl-indole-1 -carboxylic acid tert-butyl ester [200 mg, 0.426 mmol, Intermediate (10)] in tetrahydrofuran (5 mL) is added KOH (IM aqueous, 2.5 mL) and heated to 60°C for 20 hours. The solvent is removed and dissolved crade in water. The water layer is neutralized with 3N hydrochloric acid then extracted twice with ethyl acetate (20 mL).
  • Step 3 The mixture of 2-(l -tert-butoxycarbonyl- 1 H-thieno [3, 2-c]pyrazol-3 -yl)-5-(hydroxy- phenyl-methyl)-indole-l -carboxylic acid tert-butyl ester [99 mg, 0.181 mmol, Intermediate (12)] in tetrahydrofuran (2 mL) and KOH (IM aqueous, 1 mL) is stirred at 60°C under nitrogen for 22 hours. The solvent is removed in vacuo. To this slurry mixture is added water (2 mL) and brought pH to 6 by addition of 2N hydrochloric acid.
  • Step 1 To a solution of 2-(l-tert-butoxycarbonyl-lH-thieno[3,2-c]pyrazol-3-yl)-5-(hydroxy- phenyl-methyl)-indole-l -carboxylic acid tert-butyl ester [640mg, 1.17 mmol, Intermediate (12)] in Dichloromethane (25 mL) is added Dess-Martin Periodinane (677 mg, 1.69 mmol) and stirred at room temperature. After 30 minutes water (5 mL) is added and stirred for 10 minutes.
  • reaction mixture is diluted with dichloromethane (50 mL) and washed twice with a mixture of 10% Na 2 S 2 O 3 /saturated NaHCO 3 (5 mL), NaHCO 3 (10 mL), water (10 mL), brine and dried over sodium sulfate.
  • Step 2 A mixture of 5-benzoyl-2-(l-tert-butoxycarbonyl-lH-thieno[3,2-c]pyrazol-3-yl)- indole-1 -carboxylic acid tert-butyl ester [122 mg, 0.224 mmol, Intermediate (13)] in tetrahydrofuran (9 mL) and IM KOH(aqueous, 2 mL) is heated at 60°C oil bath overnight. The solvent is removed and added water (5 mL). The water layer is neutralized with 3N hydrochloric acid and extracted three times with ethyl acetate (20mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate.
  • Example 26 1 -Phenyl- 1 - 2-( 1 H-thieno .3.2-clpyrazol-3 -yl)- 1 H-indol-5-yl] -ethanol
  • Example 28 (15) Step 1.
  • 2-(l- tert-butoxycarbonyl- 1 H-thieno [3.2-c]pyrazol-3 -yl)-5-( 1 -hydroxy-propylVindole- 1 -carboxylic acid tert-butyl ester [73%, Intermediate (14)] as a white solid.
  • Step2 By proceeding in a manner similar to that described in Step 1 of Example 25 but substi tmg 2-(l-tert-bntoxycarbonyl-lH-tl ⁇ eno[3,2-c]pyrazol-3-yl)-5-(l-hydroxy-propyl)- indole-1 -carboxylic acid tert-butyl ester [Intermediate (14)]for 2-(l -tert-butoxycarbonyl- 1H- thieno[3,2-c]pyrazol-3-yl)-5-(hydroxy-phenyl-methyl)-indole-l-carboxylic acid tert-butyl ester [Intermediate (12)] there is prepared 2-( 1 -tert-butoxycarbonyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 5-propionyl-indole-l -carboxylic acid tert-butyl ester [73%, Intermediate (15)] as
  • Step 3._By proceeding in a manner similar to that described in Step 2 of Example 25 but substituting 2-( 1 -tert-butoxycarbonyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)-5-propionyl-indole- 1 - carboxylic acid tert-butyl ester [Intermediate (15)] for 5-benzoyl-2-(l -tert-butoxycarbonyl- 1 H- thieno [3, 2-c]pyrazol-3-yl)-indole-l -carboxylic acid tert-butyl ester [Intermediate (13)] there is prepared 1 - [2-( 1 H-thieno [3.2-c]pyrazol-3 -yl)- 1 H-indol-5-yl] -propan- 1 -one [94%, Example 28] is isolated as white solid; IH NMR [(CD 3 ) 2 SO)]: ⁇ 13.34 (IH, s
  • the reaction mixture is cooled to 0°C and quenched with the addition of saturated ammonium chloride (6 mL) followed by water (20 mL).
  • the aqueous layer is extracted three times with ethyl acetate (4O mL).
  • the combined extracts are washed with brine and dried over sodium sulfate and filtered over 5g silica gel cartridge and washed the cartridge with ethyl acetate(20 mL).
  • the filtrate is removed in vacuo to afford alcohol (520 mg) as an orange foam.
  • the orange foa (520 mg, 0.862 mmol) is dissolved in tetrahydrofuran (15 mL) and treated with IM KOH (aqueous, 15 mL) and heated at 70°C oil bath overnight. The solvent is removed, water added and neutralized with 3N hydrochloric acid. The product is extracted three times with, ethyl acetate (20 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate.
  • Example 30 1 -Cyclohexyl-1 - 2-fl H-thieno [3.2-c]pyrazol-3-yl)-l H-indol-5 -yl] -propan- 1 -ok enantiomer 1
  • the racemic mixture l-cyclohexyl-l-[2-(lH-thieno[3,2-c]pyrazol-3-yl)-lH-indol-5-yl]-propan- l-ol (145 mg, Example 29) is purified by chiral HPLC (Column: chiralcel OJ.
  • reaction is quenched by the addition of saturated ammonium chloride (4 mL) followed by water (4 mL).
  • the reaction mixture is extracted with ethyl acetate (120 mL). Ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (lOg silica gel cartridge, 30 - 60% ethyl acetate gradient in heptane) afforded product.
  • Example 32 A solution of 2 -( 1 -tert-butoxycarbonyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)-5-propionyl-indole- 1 - carboxylic acid tert-butyl ester [450 mg, 0.908 mmol, Intermediate (15)] in anhydrous tetrahydrofuran (25 mL) that is cooled to -78°C is added methylmagnesium bromide (IM in tetrahydrofuran, 3 mL) via syringe under nitrogen. After stirring for 30 minutes cooling bath is removed and brought the reaction to room temperature.
  • IM methylmagnesium bromide
  • reaction is cooled to — 78°C then additional 5 mL of methyl magnesium bromide is added. After 30 minutes, the cooling bath is removed and reaction temperature is brought to room temperature. After 4 hours, it is quenched by the addition of saturated ammonium chloride (6 mL). After stirring for 10 minutes, water (20 mL) is added and extracted three times with ethyl acetate (40 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate.
  • Example 33A & Example 33B (R -2-[2-(lH-Thienor3.2-c1pyrazol-3-yl)-lH-indol-5-vn-butan-2-ol and (S)-2-[2-(lH- Thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-5-yl] -butan-2-ol
  • racemic mixture 2-[2-(lH-thieno[3,2-c]pyrazol-3-yl)-lH-indol-5-yl]-butan-2-ol [Example 32] is purified by chiral HPLC (Column: chiralcel OJ.
  • Step 1 To a solution of indole-5-carboxylic acid [lOg, 62.05 mmol, Intermediate (16)] in anhydrous tetrahydrofuran (1000 mL) is added methyl lithium (1.6M in diethyl ether, 150 mL) drop wise over 6O minutes periods. The resulting precipitate is stirred at ambient temp for 40 hours.
  • Step 2 To a solution of l-(lH-indol-5-yl)-ethanone [5g, 31.41 mmol, Intermediate (17)] and 4-(dimemylamino)pyridine (39.4 mg) in tetrahydrofuran (60 mL) is added di-tert-butyl- dicarbonate (IM in tetrahydrofuran, 32 mL) drop wise at 0°C over 55 minutes. Stirred 10 minutes then water (30 mL) is added and the product extracted three times with ethyl acetate (50 mL). The combined ethyl acetate layers are washed with brine and dried over sodium sulfate.
  • IM di-tert-butyl- dicarbonate
  • Step 3 A mixture of 5-acetyl-indole-l -carboxylic acid tert-butyl ester [4.85g, 18.70 mmol, Intermediate (18)], ethylene glycol (5.0 g), pyridinium -toluenesulfonate (100 mg) in benzene (35 mL) is refl ⁇ xed under N 2 with a Dean-Stark trap for 24 hours. To this resulting dark reaction mixture is added solid NaHCO 3 (2.5 g). After stirring for 15 minutes, it is filtered under suction and washed three times with ethyl acetate (30 mL). The filtrate is washed twice with water (10 mL) and dried over sodium sulfate.
  • Step 4 To a solution of 5-(2-methyl-[l,3]dioxolan-2-yl)-indole-l-carboxylic acid tert-butyl ester [4.96 g, 16.35 mmol, Intermediate (19)] in anhydrous tetrahydrofuran (20mL) is added triisopropyl borate (4.61g, 24.51 mmol) and cooled to 0°C under N 2 . To it is added LDA (1.8 M in heptane/tetrahydrofuran /ethylbenzene, 14 mL) drop wise at 0°C over 40 minutes periods.
  • LDA 1.8 M in heptane/tetrahydrofuran /ethylbenzene
  • the crude can be purified by chromatography on silica gel by elution with ethyl acetate in heptane.
  • Step 5 In a Smith process vial (10 — 20 X ⁇ L capacity) is placed 5-acetyl-2-methyl-indole-l- carboxylic acid tert-butyl ester (436 mg, 1.44 mmol, Intermediate (20)], 3 -iodo-thieno [3 ,2- c]pyrazole-l,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester [392 mg, 0.960 mmol, Intermediate (21)], [l,r-bis(diphenylphosphino)-ferrocene]dichloropalladium with dichloromethane adduct (78 mg, 0.0955 mmol), cesium carbonate (938 mg, 2.88 mmol) and a mixture of 1,4-dioxane/water (10:2 mL).
  • the reaction tube is filled with N 2 and sealed using capping device.
  • the reaction mixture is heated at 90°C via microwave (Personal chemistry optimizer) for 10 minutes. Water is pipetted out and added solid sodium sulfate.
  • the organic phase is directly loaded onto lOg silica gel cartridge and chromatographed on 35g silica gel cartridge (20 - 30% ethyl acetate gradient in heptane) to afford 3-(5-acetyl-l-tert- butoxycarbonyl-lH-indol-2-yl)-thieno[32-c]pyrazole-1.5-dicarboxylic acid 1-tert-butyl ester 5- methyl ester (230 mg, Example 35) as white solid; IHNMR [(CD 3 ) 2 SO)]: ⁇ 8.388 (IH, s),
  • Step 5 of Example 35 was prepared as follows
  • Step 1 5-Methyl-4-nitro-thiophene-2-carboxylic acid is prepared according to Snider et al. (H. R. Snider and L. A. Carpino, J. F. Zack, Jr., J. F. Mills, J. Am. Chem. Soc, 1951, 79, 2556- 2559) from commercially available 5-methylthiophene-2-carboxylic acid and is esterified according to known processes (P. Cogolli, F. Maiolo, L. Testaferri, M. Tiecco, M. Tingoli, J.Chem. Soc, Perkin I, 1980, 1331-1335; V.M. Colburn, B. Iddon, H. Shuschitzky, J. Chem. Soc, Perkin I, 1977, 436-2441) to obtain 5-methyl-4-nitro-thiophene-2-carboxylic acid methyl ester [Intermediate (23)].
  • Step 2 5-Methyl-4-nitro-tbiophene-2-carboxylic acid methyl ester [15.09 g., 75.0 mM, Intermediate (23)] is dissolved in ethyl acetate (200 mL) to which 10% palladium on charcoal (1.03 g) is added and the mixture is shaken under 50 psi of hydrogen. The catalyst is removed by filtration and the solvent is removed leaving 4-amino-5-methyl-thiophene-2-carboxylic acid methyl ester [12.82 g., 99.8%, Intermediate (24)] as ayellow solid; MS 171.9 (100%, M + 1).
  • Step 3 A magnetically stirred mixture of potassium acetate (4.52 g, 46.1 mM) in toluene (100 mL) containing 4-an ⁇ ino-5-methyl-thiophene-2-carboxylic acid methyl ester [12.8 g, 74.7 mM, Intermediate (24)] is warmed to dissolve the amine. Acetic anhydride (13.8 mL, 124.9 mM) is added to this mixture and it is heated in an oil bath. Isoamyl nitrite (9.73 mL, 72.4 mM) is added over 30 minutes. Heating at 93 °C is continued overnight.
  • Step 4 To a suspension of 1 -acetyl- 1 H-thieno [3 ,2-c]pyrazole-5-carboxylic acid methyl ester [1.3 g, 5.79 mmol, Intermediate (25)] in methanol (30 mL) is added sodium methoxide (25 wt% in methanol). The resulting solution mixture is stirred at 60°C oil bath for 20 minutes. The oil bath is removed and stirred for 5 minutes. To this is added a solution of iodine (1.76g, 6.93 mmol) in dimethyl formamide (2 mL). The reaction mixture then heated to 60°C for 1 hour. The solvent is removed in vacuo.
  • Step 5 To a mixture of 3 -iodo-1 H-thieno [3 ,2-c]pyrazole-5-carboxylic acid methyl ester [1.5g, 4.87 mmol, Intermediate (26)] in tetrahydrofuran (120 mL) is added 4(dimemylamino)pyridine (8 mg) and di-tert-butyl-dicarbonate (IM in tetrahydrofuran, 5.3 mL) dropwise at room temperature. After stirring for 30 minutes, the solvent is removed in vacuo. The solid is suspended in a mixture of ethyl acetate, heptane and methanol and stirred for a while.
  • Example 37 3 -(5-Hydro ⁇ ymethyl- 1 H-indol-2-yl)- 1 H-thieno [3 ,2-c]pyrazole-5-carboxylic acid
  • Example 37 3 -(5-Hydro ⁇ ymethyl- 1 H-indol-2-yl)- 1 H-thieno [3 ,2-c]pyrazole-5-carboxylic acid
  • Step 1 In two separate Smith process vials (10- 20 mL capacity) are added 3-iodo-lH- thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [420 mg, 1.36 mmol, Intermediate (26)], 5-(tert-butyl-dimethyl-silanyloxymethyl)-lH-indole-2-boronic acid 1 -carboxylic acid tert-butyl ester [912 mg, 2.25 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No.
  • WO 02/32861 potassium carbonate (2M, aqueous, 2.25 mL) tefr_ ⁇ kis(triphenylphosphine)palladium(0) (87 mg, 0.0752 mmol), and a mixture of toluene/ethanol (9:3 mL).
  • the reaction tube is filled with 2 and sealed using capping device.
  • the reaction mixture is heated to 120°C using microwave (Personal chemistry optimizer) for 900 seconds. After reactions are over combined them into a flask, diluted with ethyl acetate (50 mL) and washed twice with water (10 mL), brine and dried over sodium sulfate.
  • Step 2 To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-lH-indol-2-yl]-lH- thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (1.0 g, 2.26 mmol, intermediate 28) in tetrahydrofuran (2O mL) is added sodium hydroxide (500 mg) and water (7 mL) and heated at 60°C oil bath for 16 hours. To it is added water and adjusted pH to 4 with 2N hydrochloric acid. The product is extracted with three times ethyl acetate (50 mL).
  • Step 1 To a solution of 3-iodo-lH-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [4.5g, 14.60 mmol, Intermediate (26)] in tetrahydrofuran (90 mL) is added potassium hydroxide (2.83 g, 50.44 mmol) and water (20 mL). The resulting reaction mixture is heated at 60°C oil bath under for 2 hours. The solvent is removed in vacuo and dissolved crade in water (20 mL). The water layer is acidified using 2N hydrochloric acid till pH is 5. White solid precipitated are collected and rinsed with water. The filtrate is extracted three times with ethyl acetate (50 mL).
  • Step 2 A mixture of 3-iodo-lH-thieno[3,2-c]pyrazole-5-carboxylic acid [1.05g, 3.57 mmol, Intermediate (29)], l-ethyl-3-(3-dimemylaminopropyl)carbodiimide (821 mg, 4.28 mmol), 1-hydroxybenzotriazole (482 mg, 3.57 mmol) in dimethyl formamide (45 mL) is stirred at room temperature for 10 minutes. To it is added diisopropylethylamine (1.3 mL, 7.46 mmol) followed by a solution of 2-(aminomethyl)pyridine (425 mg, 3.93 mmol) in dimethyl formamide (2 mL).
  • Step 3 In a Smith process vial (10-20 mL capacity) is added 3 -iodo-1 H-thieno [3, 2-c]pyrazole- 5-carboxylic acid (pyridin-2-ylmethyl)-amide [255 mg, 0.664 mmol, Intermediate (30)], 5-(tert- butyl-dimethyl-silanyloxymethyl)-lH-indole-2-boronic acid 1 -carboxylic acid tert-butyl ester [404 mg, 0.997 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No.
  • WO 02/32861 tefraMs(triphenylphosphine)palladium(0) (77mg, 0.0666 mmol), potassium carbonate (2M aqueous, 1 mL) and toluene/ethanol (6:3 mL).
  • the reaction tube is filled with N 2 and sealed using capping device.
  • the resulting reaction mixture is heated to 120°C using a microwave (Personal chemistry optimizer) for 1020 s.
  • the reaction mixture is diluted with ethyl acetate (50 mL), washed twice with water (10 mL), brine and dried over sodium sulfate.
  • Step 4 To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-lH-indol-2-yl]-lH- thieno [3 ,2-c]pyrazole-5 -carboxylic acid (pyridin-2-ylmethyl)-amide [258 mg, 0.498 mmol, Intermediate (31)] in tetrahydrofuran (10 mL) is added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.6 mL) and stirred at room temperature for 16 hours. Water is added and extracted three times with ethyl acetate (30 mL).
  • the reaction tube is filled with nitrogen and sealed using capping device.
  • the reaction mixture is heated at 90°C via microwave (Personal chemistry optimizer) for 20 minutes at high absorption.
  • the content is transferred to separate funnel using ethyl acetate (60 mL).
  • the ethyl acetate layer is washed with water (20 mL), brine and then dried over sodium sulfate.
  • the crude is purified using 35g silica gel cartridge (5 to 15% ethyl acetate gradient in heptane) to afford product (280 mg, 49%) as beige solid.
  • the solid (90 mg, 0. 174 mmol) is placed in a Smith vial (10 - 20 mL capacity).
  • Step 1 To a solution of lH-Indole-6-carboxylic acid methyl ester [26.65g, 146 mmol, Intermediate (33)] and 4-(dimethylarnino)pyridine (230 mg) in anhydrous tetrahydrofuran (490 mL) is added di-tert-butyl-dicarbonate (IM in tetrahydrofuran, 150 mL) drop wise over 40 minute periods. Stirred at room temperature for 100 minutes. The solvent is removed in vacuo and the mixture is redissolved in ethyl acetate (400 mL).
  • IM in tetrahydrofuran 150 mL
  • the ethyl acetate layer is washed with water (20 mL), 0.5 N hydrochloric acid (20 mL), 10% NaHCO 3 (20 mL), water (20 mL), brine and dried over sodium sulfate then filtered over 5g silica gel cartridge. The filtrate is reduced in vacuo to solid. The solid is recrystallized from a mixture of ethyl acetate and heptane to give indole- 1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester as a white solid (18.53g).
  • the recrystallisation step is repeated to give a second crop of indole- 1,6-dicarboxylic acid 1- tert-butyl ester 6-methyl ester as a white solid (16.3g).
  • a third crop (5.17g) of indole-1,6- dicarboxylic acid 1-tert-butyl ester 6-methyl ester is obtained from the mother liquor by silica gel chromatography; total yield of indole- 1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester [40g, 100%, Intermediate (34)]; 1HNMR (cdcl 3 ) ⁇ 8.886 (IH, s), 7.937 (IH, d), 7.764 (IH), 7.621 (IH, d), 6.636 (IH), 3.972 (3H, s), 1.734 (9H, s); LC/MS: 276 (M+H).
  • Step 2 A solution of indole- 1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester [13.32 g, 48.38 mmol, Intermediate (34)] and triisopropyl borate (13.65g, 72.58 mmol) in anhydrous tetrahydrofuran (200 mL) is cooled to 0°C under nitrogen. To it is added LDA (1.8 M in heptane/ tetrahydroftiran /ethylbenzene, 35 mL) drop wise over 40 minute periods. Stirred at 0°C for 1.5 hours. The reaction is quenched by the addition of 3N hydrochloric acid until pH ⁇ 4 on pH paper.
  • LDA 1.8 M in heptane/ tetrahydroftiran /ethylbenzene
  • Step 3 A mixture of 6-methoxycarbonyl- l-tert-butoxycarbonyl-indole-2-boronic acid (3.24 g, 10.15 mmol Intermediate (35)], 3 -iodo-thieno [3, -c]pyrazole-l -carboxylic acid tert-butyl ester [2.37g, 6.77 mmol, Example 5B above], [l, -bis(diphenylphosphino)- ferrocene]dichloropalladium with dichloromethane adduct (552 mg, 0.676 mmol), cesium carbonate (6.61g, 20.29 mmol) and amixture of 1 ,4-dioxane/water (40:10 mL).
  • the resulting mixture is heated at 82°C oil bath for 3 hours under nitrogen.
  • the reaction mixture is poured into ethyl acetate (300 mL).
  • the ethyl acetate layer is washed twice with water (20 mL), brine and dried over sodium sulfate.
  • the crude reaction product is purified on 110 g silica gel cartridge (3% of a mixture of ethyl acetate in methylene chloride and 97% heptane) to afford 2-(l -tert-butoxycarbonyl- 1 H-thieno[3 ,2-c]pyrazol-3-yl)-indole- 1 ,6-dicarboxylic acid 1 -tert- butyl ester 6-methyl ester [1.68g, 50%, Intermediate (36)] as white foam ;1H NMR [(CD 3 ) 2 SO)]: ⁇ 8.975 (IH, s), 8.017 (IH), 7.669 (IH), 7.583 (IH), 7.379 (IH), 7.048 (IH, s),
  • reaction is not completed (TLC) and added cyclopropylmagnesium bromide (6.0 mL). The solublized reaction mixture is then stirred overnight. The reaction is quenched at 0°C by the addition of saturated ammonium chloride. The reaction mixture is partitioned between diethyl ether and water. The diethyl ether layer is washed with brined and dried over magnesium sulfate. The crude is chromatographed on lOg silica gel cartridge (30 - 50% ethyl acetate gradient in heptane) to afford product (120 mg).
  • the product is recrystallized as follows: In a Smith vial, a mixture of solid (120 mg) and ethyl acetate (2 mL) is heated at 70°C using microwave (Personal chemistry optimizer) for 240 seconds at normal absorption.
  • microwave Personal chemistry optimizer
  • Step 1 A solution of lithium diisopropylamide (1.8M, 50.5 ml, 90.9mmol, 2.5eq) was added to a solution of indole- 1,6-dicarboxylic acid, 1-tert-butyl ester-6-methyl ester [lOg, 38.4mmol, Intermediate (34)] in tetrahydroiuran (160ml) at -78°C. The resulting mixture was stirred for 2 hours at -78°C before a solution of trimethyltin chloride in tetrahydrofuran (IM, 145.5ml, 4eq) was added.
  • IM trimethyltin chloride in tetrahydrofuran
  • Step 2 A solution of trimethyl(indole- 1,6-dicarboxylic acid, 1-tert-butyl ester-6-methyl ester)tin [7.5g, 17.1mmol, 2eq, Intermediate (37)] in dioxane (30ml) was added in two equal portions over 2 hours to a solution of 3 -iodo-thieno [3, 2-c]pyrazole-l -carboxylic acid tert-butyl ester [3g, 8.6mmol leq, Example 5B above], copper iodide (171mg, 0.43mmol, O.leq) and tefra s(triphenyl-phosphine) palladium (497mg, 0.43mmol, 0.05eq) in dioxane.
  • Step 3 The mixture of 2-(l H-thieno [3, 2-c]pyrazol-3-yl)-lH-indole-6-carboxylic acid [lOOmg, 1.5eq, Intermediate (38)], PS-DCC (2eq) and HOBT (1.7eq) in DCM (5ml) was shaken for 15minutes. Then l-benzo[l,3]dioxol-5-ylmethyl-piperazine was added and the reaction mixture was shaken at room temperature overnight. PS-trisamine (4eq) was added and the mixture was shaken at room temperature overnight. The resin was filtered, washed with DCM and the filtrate was concentrated.
  • Step 1 To a stirred solution of 3,4-dinitrophenol (2g, 10.9mmol, leq) in dimethyl formamide (40ml), chloropropyl piperidine hydrochloride (2.8g, 14.2mmol, 1.3eq) and potassium carbonate (3.2g, 22.9mmol, 2. leq) were added. The mixture was heated to 100°C for 4 hours and the reaction was cooled to room temperature.
  • Step 2 1- [3 -(3 ,4-Dinitro-phenoxy)-propyl] -piperidine [3.2 g] was dissolved in methanol (20ml) and palladium on carbon (1.12g, 10%) and forrnic acid (2ml) was added. The mixture was hydrogenated at 50psi for 3 hours and the mixture was filtered through celite. The filtrate was concentrated to afford 4-(3 -piperidin- 1 -yl-propoxy)-benzene- 1 ,2-diamine [2.45 g, Intermediate (39)] product as a dark oil. LC/MS: 250 (M+H). Step 3.
  • Step 4 To a stirred solution of 6-(3 -piperidin- 1 -yl-propoxy)- 1 H-benzoimidazole [2.6g, Intermediate (40)] in dimethyl formamide (20ml), sodium hydride (0.44g, 60% dispersion in oil) in two portions was added under nitrogen folio wed by benzyl-chloromethyl ether (1.89g) in dimethyl formamide (5ml) in a dropwise manner. The reaction mixture was stirred at room temperature overnight, then poured into water (150ml) and then extracted three times with ethyl acetate (50ml). The combined extracts were ⁇ vashed with water and brine, dried over magnesium sulfate, filtered and concentrated.
  • Step 5 l-benzyloxymethyl-6-(3 -piperidin- 1 -yl-propoxy)- 1 H-benzoimidazole [460mg, Intermediate (41)] was dissolved in tefrahydrofuran (15ml, dry) under nitrogen and the solution was cooled to 0°C. n-Butylithium (2ml, 1.3mmol, 2.4eq) was added and the solution was stirred for 0.5 hour. Then, the mixture was warmed to room temperature, and a second portion of n-butylithium (1ml, 1.2eq) was added and stirring was continued for 0.5 hour.
  • Step 6 A mixture of [1 -benzyloxymethyl-6-(3 -piperidin- 1 -yl-propoxy)- 1 H-benzoimidazol-2- yl]-(3-bromo-benzo[b]thiophen-2-yl)-methanone [40mg, Intermediate (42)], benzophenone hydrazone (18mg, 1.4eq), Pd(OAc) (0.9mg, 0.05eq)), DPPF(3.8mg, O.leq) and cesium carbonate (33.7mg, 1.6eq) in 5ml toluene under nitrogen was heated at 90°C overnight.
  • Step 7 A mixture of [3-(N'-bei____hyd_ylidene-hydrazino)-benzo
  • Example 56 1 - (3 - [2-(5 -Phenyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-6-yloxy] -propyl ⁇ -piperidin-3 -ol
  • Step 2 To a mixture of l-(5-phenyl-thieno[3,2-c]pyrazol-l-yl)-ethanone [3.82 g, 15.8 mmol, Intermediate (44)] and ethanol (50 mL) was added 6 N hydrochloric acid (50.0 mL, 300 mmol) in one portion and the resulting mixture heated at 70° C. After 18 hours, the reaction was cooled to ambient temperature and neutralized with 25% aqueous potassium carbonate. The mixture was diluted with water (200 mL) and aged at 0°C for 1 hour.
  • Step 3 Crashed KOH (1.09 g, 6.49 mmol) was added in one portion to a stirred mixture of 5-phenyl-lH-thieno[3,2-c]pyrazole [1.30 g, 6.49 mnxol, Intermediate (45)], iodine (2.47 g, 9.73 mmol), and dimethylformamide (15 mL) under nitrogen at room temperature and the dark reaction was stirred at room temperature. After 3 hours, 10% aqueous NaHSO 3 (40 mL) was added with stirring. The resulting slurry was diluted with water (40 mL) and the mixture stirred at room temperature for 5 minutes.
  • Step 4 4-Dimethylaminopyridine (195 mg, 1.60 mmol) was added to a mixture of 3-iodo-5- phenyl-1 H-thieno [3, 2-c]pyrazole [2.60 g, 7.97 mmol, Intermediate (46)], di-tert-butyl dicarbonate (2.78 g, 12.7 mmol), and anhydrous dichloromethane (30 mL) at room temperature with stirring. The resulting solution was stirred at room temperature. After 16 hours, the reaction was diluted with dichloromethane (20 mL), washed with water (50 mL) and brine (40 mL) successively, dried over magnesium sulfate, and concenfrated under reduced pressure to an amber oil.
  • Step 5 A mixture of 5-(tert-butyl-dimethyl-silanyloxymethyl)-lH-indole-2-boronic acid 1- carboxylic acid tert-butyl ester [2.39 g, 6.11 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No.
  • Step 6 To a solution of 2-(l-tert-butoxycarbonyl-5-phenyl-lH-thieno[3,2-c]pyrazol-3-yl)-6- (tert-butyl-dimethyl-silanyloxy)-indole-l -carboxylic acid tert-butyl ester [2.44 g, 3.78 mmol, Intermediate (48)] in tetrahydrofuran (25 mL) at 0°C was added tetrabutylammonium fluoride (4.20 mL of a IM THF solution, 4.20 mmol) in one portion with stirring.
  • tetrabutylammonium fluoride 4.20 mL of a IM THF solution, 4.20 mmol
  • Step 7 A mixture of 2-(l-tert-butoxycarbonyl-5-phenyl-lH-thieno[3,2-c]pyrazol-3-yl)-6- hydroxy-indole-1 -carboxylic acid tert-butyl ester [950 mg, 1.79 mmol, Intermediate (49)], cesium carbonate (1.75 g, 5.37 mmol), and 1,3-dibromopropane (6.0 mL) was heated at 90°C under nitrogen. After 1.5 hours, the mixture was cooled to ambient temperature, filtered, and the insolubles washed twice with dichloromethane (10 mL). The filtrate was concentrated in vacuo to yield a cloudy oil.
  • Step 8 A mixture of 6-(3-bromo-propoxy)-2-(l-tert-butoxycarbonyl-5-phenyl-lH- thieno [3, 2-c]pyrazol-3-yl)-indole-l -carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate (50)], 3-hydroxypiperidine (73.0 mg, 0.722 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (39.0 mg, 0.235 mmol), and anhydrous acetonitrile (5 mL) was heated at 70°C with shaking at 200 rpm.
  • Trituration ofthe solid with methanol ether (1 :4) provided 1 - ⁇ 3 - [2-(5 -phenyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H- indol-6-yloxy]-propyl>-piperidin-3-ol [163 mg, 75%, Example 56] as an off-white powder.
  • Step 1 A mixture of l-(thieno[3,2-c]pyrazol-l-yl)-ethanone (5.00 g, 30.1 mmol), N- bromosuccinimide (16.1 g, 90.4 mmol), and chloroform (100 mL) was heated at 50°C under nitrogen for 5 hours. The orange mixture was stirred at room temperature for an additional 17 hours. The red-orange mixture was filtered, the insolubles washed twice with dichloromethane (60 mL). The filtrate was washed with 10% aqueous NaHSO 3 (60 mL) and then twice with water (60 mL), then dried over magnesium sulfate, and concentrated under reduced pressure.
  • Step 2 A mixture of l-(5-bromo-thieno[3,2-c]pyrazol-l-yl)-ethanone [12.0 g, 49.0 mmol Intermediate (51)], 1,4-dioxane (120 mL), and 2 M aqueous potassium carbonate (80.0 mL) was stirred at 95°C under nitrogen. After 20 hours, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (200 mL). The mixture was washed twice with water (100 mL) and brine (100 mL) successively, dried over magnesium sulfate, and concentrated in vacuo.
  • Step 3 A solution of 5-bromo-lH-thieno[3,2-c]pyrazole [8.00 g, 39.4 mmol Intermediate (52)] in dimethylformamide (50 mL) was added dropwise to a room temperature mixture of sodium hydride (1.74 g, 60% oil dispersion, 43.5 mmol) and dimethylformamide (10 mL) over 5 minutes and the resulting mixture stirred at room temperature for 30 minutes.
  • 2-(Trimethylsilyl)ethoxymethyl chloride (9.85 g, 5.91 mmol) was added dropwise and the resulting white slurry was stirred at room temperature for 21 hours.
  • the reaction mixture was diluted with water (300 mL) and extracted twice with ethyl acetate (125 mL).
  • the oil was chromatographed on silica, eluting first with 5% ethyl acetate/dichloromethane and then 10% ethyl acetate/ dichloromethane to afford a mixture of 5-(3-methoxy-phenyl)-l-(2-trimethylsilanyl- ethoxymethyl)- 1 H-thieno [3 ,2-c]pyrazole and 5-(3 -memoxy-phenyl)-2-(2-trimethylsilanyl- ethoxymethyl)-2H-thieno[3,2-c]pyrazole [4.58 g, 77%] as a cloudy amber oil.
  • Step 4 Crushed potassium hydroxide (1.35 g, 24.1 mmol) was added in one portion to a solution of 5-(3-methoxyphenyl)-lH-thieno[3,2-c]pyrazole [1.85 g, 8.03 mmol, Intermediate (53)] and dimethylformamide at 0°C with stirring. After 10 minutes, iodine (3.05 g, 12.0 mmol) was added in one portion and the dark reaction was stirred at 0°C for 30 minutes and then at room temperature for 5 hours. The reaction was quenched with 10% aqueous NaHSO 3 (100 mL), the resulting white mixture diluted with water (100 ml) and the mixture aged at 5°C overnight.
  • Step 5 Added 4-dimemylaminopyridine (102 mg, 0.835 mmol) to a room temperature mixture of 3-iodo-5-(3-methoxyphenyl)-lH-thieno[3,2-c]pyrazole [1.50 g, 4.21 mmol, Intermediate (54)], di-tert-butyl dicarbonate (1.38 g, 6.32 mmol), and anhydrous dichloromethane (40 mL) with stirring. The resulting solution was stirred at room temperature. After 20 h, the reaction was washed with water (2 x 30 mL), dried over magnesium sulfate, and concenfrated under reduced pressure to a tan solid.
  • Step 6 A mixture of 5-(tert-butyl-dimethyl-silanyloxymethyl)-l H-indole-2-boronic acid 1- carboxylic acid tert-butyl ester [1.67 g, 4.27 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No.
  • Step 7 To a solution of 2-[l-tert-butoxycarbonyl-5-(3-methoxy-phenyl)-lH-thieno[3,2- c]pyrazol-3-yl]-6-(tert-butyl-dimethyl-silanyloxy)-indole-l -carboxylic acid tert-butyl ester [1.70 g, 2.52 mmol, Intermediate (56)] in tetrahydrofuran (20 mL) at 0°C was added tetrabutylammonium fluoride (2.80 mL of a IM tefrahydrofuran solution, 2.80 mmol) in one portion with stirring.
  • Step 8 A mixture of 2-[l-tert-butoxycarbonyl-5-(3-methoxy-phenyl)-lH-thieno[3,2-c]pyrazol- 3 -yl]-6-hydroxy-indole-l -carboxylic acid tert-butyl ester [1.19 g, 2.12 mmol, Intermediate (57)], cesium carbonate (2.07 g, 6.35 mmol), and 1,3-dibromopropane (8.0 mL) was heated at 75°C under nitrogen. After 6 hours, the mixture was cooled to ambient temperature and let stand overnight. The mixture was filtered, and the insolubles washed twice with dichloromethane (10 mL).
  • Step 1 4-Dimethylaminopyridine (102 mg, 0.835 mmol) was added to a mixture of 5- methoxy-pyrrolo[3,2-b]pyridine (4.50 g, 30.4 mmol, prepared according to procedures described in Liebigs Ann. Chem. 1988, 203-208), di-tert-butyl dicarbonate (10.7 g, 49.0 mmol), and anhydrous dichloromethane (100 mL) at room temperature with stirring. The resulting solution was stirred at room temperature overnight. The reaction was washed with water (75 mL) and brine (75 mL) successively, dried over magnesium sulfate, and concenfrated under reduced pressure to an amber oil.
  • Step 2 A solution of tert-butyllithium (15.0 mL, of a 1.5 M solution in pentane, 22.5 mmol) was added in portions to a solution of 5-methoxy-pyrrolo[3,2-b]pyridine- 1 -carboxylic acid tert- butyl ester [4.66 g, 18.8 mmol, Intermediate (60)] in anhydrous tefrahydrofuran (85 mL) under nifrogen at -78°C over 4 minutes. The resulting red reaction was stirred at — 78°C for 41 - Ill - minutes.
  • Triisopropyl borate (8.70 mL, 37.7 mmol) was added over 2 minutes and the red- brown reaction stirred at -78°C for 20 minutes. The reaction was warmed to O°C, stirred for 2.5 hours, and then water (50 mL) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. The aqueous mixture was basified with 5 N aqueous sodium hydroxide to pH 14. The mixture was extracted twice with ethyl acetate (30 mL). The aqueous layer was cooled to 0°C, acidified with 10% aqueous KHS0 4 to pH 4, and the resulting slurry aged at 0°C for 15 minutes.
  • Step 3 A mixture of 5-methoxy-lH-indole-2-boronic acid 1-carboxylic acid tert-butyl ester [600 mg, 2.05 mmol, Intermediate (61)], 3 -iodo-thieno [3, 2-c]pyrazole- 1-carboxylic acid tert- butyl ester [600 g, 1.71 mmol, Example 5B], cesium carbonate (2.23 g, 6.84 mmol), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (93 mg, 0.114 mmol), 1,4-dioxane (12 mL), and water (3.0 mL) was purged with nifrogen and then heated at 90°C with stirring under nifrogen.
  • Step 4 To a solution of 2-(l-tert-butoxycarbonyl-lH-thieno[3,2-c]pyrazol-3-yl)-5-methoxy- pyrrolo [3 ,2-b]pyridine- 1-carboxylic acid tert-butyl ester [250 mg, 0.531 mmol, Intermediate (62)], anisole (1.0 mL), and dichloromethane (1.0 mL) at ambient temperature was added trifluoroacetic acid (1.0 mL) and the resulting solution heated at 45°C .
  • Example 61 3 -Bromo-6-(3 -piperidin- 1 -yl-propoxy)-2-( 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indole.
  • Step 2 To a solution of 2-(l -tert-butoxycarbonyl- 1 H-thieno [3, 2-c]pyrazol-3 -yl)-6-(tert-butyl- dimethyl-silanyloxy)-indole- 1-carboxylic acid tert-butyl ester [0.87 g, 1.51 mmol, Intermediate (63)] in chloroform (15 mL) was added bromine (95 ⁇ L, 1.81 mmol). The reaction was stirred at room temperature overnight. A sodium bisulfite solution was added until the orange mixture turned to pale yellow. The mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated.
  • Step 3 To a solution of 3 -bromo-2-( 1 -tert-butoxycarbonyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)-6- (tert-butyl-dimethyl-silanyloxy)-indole- 1-carboxylic acid tert-butyl ester [0.32 g, 49mmol, Intermediate (64)] in tefrahydrofuran at 0°C was added a 1.0 M TBAF solution in tetrahydrofuran (0.51mL, 0.51mmol). The resulting solution was stirred at 0°C for 30 minutes. The solvent was removed.
  • Step 4 To 3 -bromo-2-(l -tert-butoxycarbonyl- 1 H-thieno [3, 2-c]pyrazol-3-yl)-6-hydroxy-indole- 1 -carboxylic acid tert-butyl ester [0.22g, 0.40mmol, Intermediate (65)] in 1,3 dibromopropane (4mL) was added cesium carbonate (0.33g, l.Ommol). The resulting suspension was stirred at 75°C for 1 hour then filtered. The insoluble was filtered off. The filtrate was concentrated.
  • Trifluoroacetic acid (0.5 mL) was added. The resulting bright yellow solution was stirred at 40°C overnight as it turned to a greenish solution. It was directly loaded onto a cationic ion exchange column (SCX mega bond elut from VARIAN, 5g), washed with methanol and eluted with 1.0 M ammonia in methanol. The appropriate fractions were combined and concentrated.
  • SCX mega bond elut from VARIAN, 5g
  • Example 62 (3 - [6-(3 -Piperidin- 1 -yl-propoxy)- 1 H-indol-2-yI) - 1 H-thieno [3.2-c]pyrazol-5-yl> -methanol
  • Step 1 To a solution of (4-bromo-thiophen-2-yl)-methanol (25g, 130mmol) in dichloromethane was added imidazole (9.7g, 142mmol) followed by tert-butyldimethylsilyl chloride (23.4g, 156mmol). The white suspension was stirred at room temperature for 30 minutes. The insoluble was filtered off. The filtrate was concentrated.
  • Step 3 To a solution of 3-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiophene-2- carbaldehyde [30.1g, 89.7mmol, Intermediate (68)] in ethanol (350 mL) was added benzophenone hydrazone (20g, 104.7mmol). The resulting yellow solution was stirred at reflux for 6 hours.
  • Step 4 To a solution of N-benzhydrylidene-N'-fl-P-bromo-S- ⁇ ert-butyl-dimethyl- silanyloxymethyl)-thiophen-2-yl]-methylidene]-hydrazine [41.2g, 80.2mmol, Intermediate (69)] in toluene (500 mL) were added benzophenone hydrazone (18.9g, 96.2 mmol), cesium carbonate (44.3g, 136.3 mmol) then l,l'-diphenylphosphinoferrocene (6.66g, 12 mmol), and palladium acetate (1.35g, 6 mmol). The orange mixture was stirred at 90°C for 20 hours.
  • Step 5 To a solution of (lH-thieno[3,2-c]pyrazol-5-yl)-methanol [3.2g, 20.8mmol, Intermediate (70)] in solution in dimethyl formamide (40mL) were added potassium hydroxide (3.5g, 62.3 mmol) and iodine (7.9 g, 31.1 mmol). The mixture was stirred at room temperature for 5 hours. A concenfrated solution of sodium bisulfite in water was added until the orange color disappeared. The resulting mixture was exfracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated.
  • potassium hydroxide 3.5g, 62.3 mmol
  • iodine 7.9 g, 31.1 mmol
  • Step 6 To (3-iodo-lH-thieno[3,2-c]pyrazol-5-yl)-methanol [2.89g, 10.3mmol, Intermediate (71)] in dimethyl formamide (20 mL) was added imidazole (1.4g, 20.6mmol) and tert- butyldimethylsilyl chloride (2.63g, 17.5mmol). The resulting solution was stirred at room temperature for 5 minutes. It was then diluted with water and was extracted twice with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concenfrated.
  • Step 9 To a solution of 2-[l-tert-butoxycarbonyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-lH- 1hieno[3,2-c]pyrazol-3-yl]-6-(tert-butyl-dime yl-sil-inyloxy)-indole-l-carboxylic acid tert- butyl ester [3.2g, 4.5 mmol, Intermediate (75)] in tefrahydrofuran (30mL) at 0°C was added a 1.0 M TBAF solution in tetrahydrofuran. The green solution was stirred at 0°C until the reaction is complete and was then diluted with water.
  • Step 10 To a suspension of 2-(l-tert-butoxycarbonyl-5-hydroxymethyl-lH-thieno[3,2- c]pyrazol-3-yl)-6-hydroxy-indole- 1-carboxylic acid tert-butyl ester [1.45g, 2.99mmol, Intermediate (76)] in 1,3 dibromopropane (5mL) was added cesium carbonate (2.43g, 7.48mmol). The suspension was stirred at 80°C for 3 hours. It was allowed to cool down to room temperature. The insoluble was filtered off.
  • Step 11 To 6-(3-bromo-propoxy)-2-(l-tert-butoxycarbonyl-5-hydroxymethyl-lH-thieno[3,2- c]pyrazol-3-yl)-indole- 1-carboxylic acid tert-butyl ester [160mg, 0.26mmol, Intermediate (77)] in acetonitrile (4mL) were added polymer supported DIEA (3.86 mmol g, 135 mg, 0.52 mmol) and piperidine (52 ⁇ L, 0.52 mmol). The mixture was stirred gently at 75°C for 3 hours. The PS-DIEA was filtered and the solvent was removed.
  • Step 1 To 6-(3 -bromo-propoxy)-2-( 1 -tert-butoxycarbonyl-5-hydroxymethyl- 1 H-thieno [3,2- c]pyrazol-3-yl)-indole- 1-carboxylic acid tert-butyl ester [990 mg, 1.63mmol, Intermediate (77)] in acetonitrile (20mL) were added polymer supported DIEA (3.83mmol/g, 850 mg, 3.26mmol) and piperidine (0.32mL, 3.26mmol). The mixture was stirred gently at 60°C for 4 hours. The PS-DEEA was filtered and the solvent was removed.
  • the residue was chromatographed through silica gel (dichloromethane/l.OM ammonia in methanol, 90/10). The appropriate fractions were combined and concenfrated.
  • the residue was dissolved into dichloromethane (2mL) and anisole (0.5mL). Trifluoroacetic acid (0.5mL) was added. The solution was stirred at 45°C for 3 hours. It was then directly loaded onto a cationic ion exchange column (Varian Mega Bond Elut SCX, 5g) washed with methanol and eluted with 1.0M ammonia in methanol. The appropriate fractions were combined and concenfrated.
  • Example 64 2- ⁇ 5 - [4-f 4-Fluoro-phenyl)-piperazin- 1 -ylmethyl]- 1 H-thieno [3 ,2-c]pyrazol-3 -yl -6-(3 - piperidin- 1 -yl-propoxy)- 1 H-indole
  • Step 1 To 5 -(tert-butyl-dimethyl-silanyloxymethyl)-3 -iodo-thieno [3 ,2-c]pyrazole- 1-carboxylic acid tert-butyl ester [410mg, 0.83mmol, Intermediate (73)] in tefrahydrofuran (5mL) was added a l.OM TBAF solution in tefrahydrofuran (0.92mL, 0.92mmol) at 0°C. The solution was stirred at 0°C for 1 hour.
  • Step 3 To 3 -iodo-5-memanes ⁇ ufonyloxymethyl-thieno [3 ,2-c]pyrazole- 1-carboxylic acid tert- butyl ester [210mg, 0.46 mmol, Intermediate (81)] in dichloromethane (3mL) were added triethylamine (70 ⁇ L, 0.55mmol), and piperidine (55 ⁇ L, 0.55mmol). The mixture was stirred at room temperature for 1 hour.
  • Step 4 To 3-iodo-5-piperidm-l-ylmethyl-thieno[3,2-c]pyrazole-l-carboxylic acid tert-butyl ester [390mg, 0.87mmol, Intermediate (82)] in 1,4-dioxane (8mL) were added 5-(tert-butyl- dimethyl-silanyloxymethyl)-lH-indole-2-boronic acid 1-carboxylic acid tert-butyl ester (450mg, 1.13mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No.
  • Step 6 To 2-(l-tert-butoxycarbonyl-5-piperidin-l-ylmemyl-lH-thieno[3,2-c]pyrazol-3-yl)-5- hydroxymethyl-indole- 1-carboxylic acid tert-butyl ester [280mg, 0.50mmol, Intermediate (84)] in a mixture of tetrahydrofuran (5mL) and water (lmL) was added sodium hydroxide (150mg, 3.75mmol). The mixture was stirred at 65°C overnight. It was diluted with ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate.
  • Example 69 1 - (3 - [2-(5-Benzyloxymethyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-6-yloxy] -propyl ⁇ - piperidin-4-ol
  • Example 69 1 - (3 - [2-(5-Benzyloxymethyl- 1 H-thieno [3 ,2-c]pyrazol-3 -yl)- 1 H-indol-6-yloxy] -propyl ⁇ - piperidin-4-ol
  • Step 1 To (4-bromo-thiophen-2-yl)-methanol (18.8g, 97.4mmol, Intermediate (85)] in tetrahydrofuran (200mL) was added sodium hydride (3.9g, 97.4mmol) at 0°C under nifrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Tetrabutylammonium iodide (3.6g, 9.7mmol) was added followed by benzyl bromide (11.6mL, 97.4mmol). The mixture was stirred at room temperature for 1 hour. Water was added. The resulting mixture was exfracted with diethyl ether. The ether layer was dried over magnesium sulfate and concenfrated.
  • Step 2 To 2-benzyloxymethyl-4-bromo-thiophene (29.2g, 103mmol, Intermediate (86)] in tefrahydrofuran (lOOmL) was added dropwise a 1.8M solution of LDA in tefrahydrofuran (63mL, 113mmol) at 0°C under nitrogen atmosphere. The solution was stirred at 0°C for 30 minutes. Then N-formyl piperidine (13.75mL, 127mmol) was added and the reaction was stirred at 0°C for 45 minutes, at room temperature for 15 minutes, and was quenched with saturated aqueous ammonium chloride. The mixture was exfracted with ethyl acetate.
  • Step 3 To (5-be_ ⁇ zyloxymethyl-3-bromo-thiophene-2-carbaldehyde (23.2g, 74.6mmol, Intermediate (87)] in ethanol was added hydrazone benzophenone (16.1g, 82mmol). The mixture was stirred at 80°C overnight. The solvent was removed.
  • Step 4 To N-benzhydrylidene-N'-[l-(5-benzyloxymemyl-3-bromo-thiophen-2-yl)- methylidene] -hydrazine (34g, 69.5mmol, Intermediate (88)] in toluene (500mL) were added hydrazone benzophenone (16.4, 83.4mmol), cesium carbonate (38.4g, 118.2mmol), 1,1'diphenylphosphinoferrocene (5.8g, 10.4mmol), and palladium (ft) acetate (1.17g, 5.2mmol). The suspension was stirred at 90°C under nitrogen atmosphere until reaction is complete. The solvent was removed.
  • the residual oil was chromatographed (ethyl acetate/n- heptane, 10/90 as eluant) to product an orange oil. It was dissolved in ethanol (350mL). Concentrated hydrochloric acid (lOOmL) was added. The dark mixture was stirred at 80°C for 15 hours then diluted with water. It was exfracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concenfrated.
  • Example 5E substituting 2-(5-benzyloxymethyl-l -tert-butoxycarbonyl- 1 H-thieno [3 , 2- c]pyrazol-3-yl)-6-hydroxy-indole- 1-carboxylic acid tert-butyl ester [Intermediate (93)] for 2-( 1 -tert-butoxycarbonyl- 1 H-thieno [3 ,2c]pyrazol-3 -yl)-5-hydroxy-indole- 1 -carboxylic acid tert-butyl ester.
  • Step 1 To 5-benzyloxymethyl-3-iodo-thieno[3,2-c]pyrazole-l-carboxylic acid tert-butyl ester (1.78g, 3.78mmol, Intermediate (91)] in 1,4-dioxane were added successively copper iodide (0.07g, 0.38mmol), [l,l'-bis(diphenylphosph_no)-ferrocene] dichloropalladium(II) (complex with dichloromethane (1:1)) (0.14g, 0.19mmol), and trimethyl(indole- 1,6-dicarboxylic acid, 1- tert-butyl ester-6-methyl ester)tin [4.1g, 9.45mmol, Intermediate (37)].
  • the mixture was stirred at 90°C for 5 hours then at room temperature for 2 hours. It was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated.
  • Step 2 To 2-(5-be ⁇ _zyloxymethyl-l-tert-butoxycarbonyl-lH-thieno[3,2-c]pyrazol-3-yl)-mdole- 1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester [0.35g, 0.68mmol, Intermediate (95)] in tefrahydrofuran (5mL) at -78°C under nifrogen was added a 1.OM solution of ethylmagnesium bromide in tefrahydrofuran (1.7mL, 1.7mmol). The mixture was stirred at -78°C for 1 hour.
  • Example 90 F2-(lH-thieno f3,2-c] pyrazol-3 -yl)- lH-indol-6-yl] -tetrahydro-pyran-4-ol
  • Example 91 3-(2-r5-(l-hvdroxy-l-methyl-ethyl)-lH-thienor3.2-c]pyrazol-3-yll-lH-indol-6-yl)-pentan-3-ol
  • Anti-CD3 stimulated IL-4 Assay from Murine splenocytes Anti-CD3 stimulated IL-4 Assay from Murine splenocytes.
  • the tyrosine kinase ITK is involved in intracellular signaling events induced by several lymphocyte surface receptors. Since HK deficient mice show an impairment in IL-4 production from T cells, a cell based assay for IL-4 production is used to measure the cellular potency of the HK inhibitors of the present invention. In this assay the level of IL-4 is measured from the media of anti-CD3-stimulated murine splenocytes, and the ability of compounds of the present invention to inhibit this response is determined.
  • Spleens from the mouse strain BALB/c are isolated and used to prepare a suspension of mixed splenocytes.
  • the spleens are homogenized with cell strainer (Falcon Cat#352350 and 5ml syringe) in RPIvfl media.
  • the mixture is spun down, and the pellets are suspended in 3ml of Red Blood Cell Lysing Buffer ( Sigma Cat#7757) and left for 10 minutes at room temperature. Cells are spun down again, and resuspended in RPIvfl with 10% FBS and passed through cell strainer. Total cell numbers are determined with hemocytometer.
  • Splenocytes are adjusted to a cell density of 10 million per ml of RPMI medium supplemented with 10% Foetal Bovine Serum (FBS) and lOOuls of the suspension plated out per well of a 96 round bottom plate. 50uls of RPMI medium containing 4x the final concentration of test compound is added per well. For IC50 determination the following concentrations of compound are used. The starting concentration is lOuM and 7 series of 1:3 dilutions are followed, and each compound concentration is set up in triplicate wells. 50ul of 4x concentration are added.
  • FBS Foetal Bovine Serum
  • Cell cultures are then stimulated by addition of 50 ul of a 4ug/ml solution of anti-CD3 antibody, ( BD Bioscience Cat# 553166) made up in RPMI plus 10% FBS media, and incubated in a 37°C CO2 incubator for 3 days. At the end of the 3 day incubation, culture medium is taken and 50 uls used to assay IL-4 production by ELISA (IL-4 ELISA kit from R&D Systems, city. Cat# M4000 kit) according to the standard conditions described by the manufacturer.
  • ELISA IL-4 ELISA kit from R&D Systems, city. Cat# M4000 kit
  • IL-4 levels are plotted as a function of compound concentration.
  • concentration of compound resulting in 50% inhibition of IL-4 termed IC50(_L-4) is determined from the resulting curve.
  • the transfer of radioactive [ ⁇ - 33 P] phosphate from [ ⁇ - 33 P]ATP to HK during the autophosphorylation of HK is measured by scintillation counting.
  • Streptavidin-coated FlashPlate PlusTM 384 well microplates (PerkinElmer Life Sciences) are designed for in-plate radiometric assays. The interior of each well is permanently coated with a thin layer of scintillant and a covalently bound layer of Streptavidin.
  • HK is incubated with [ ⁇ - 33 P] ATP, biotinylated anti-MBP antibody (Cell Signaling TechnologyTM) and test compounds in a 384- well Streptavidin- coated FlashPlate.
  • the biotinylated anti-MBP binds tightly to the MBP-tagged HK and cross-links it to Streptavidin on the plate surface.
  • Unreacted 33 P-ATP is washed away and 33 P- ⁇ hosphorylated HK is measured when the [ ⁇ - 33 P] incorporated into HK stimulates the scintillant on the well to emit light. Radioactivity is assessed in a Packard TopCount scintillation counter. Reagents are pipetted and dispensed using Beckman Biomek robotic equipment.
  • Test compounds (2 ⁇ l per well) are pre-diluted from lmM 100% dimethyl sulfoxide solutions into water containing 30% dimethyl sulfoxide to produce dose response curves (10 point curves from (final) 30 ⁇ M to ⁇ 1 nM); all tests are performed in duplicate. Background binding is assessed by substituting the enzyme inhibitor EDTA (25mM final concentration) for test compound and maximal binding is assessed by inclusion of assay buffer instead of compound. Test compounds are added to the wells first (2 ⁇ l) followed by 10 ⁇ l enzyme solution in assay buffer. After 30 minutes pre-incubation, all other reagents are added in a 10 ⁇ l volume.
  • the final reagent concentrations/well are as follows: 20 nM enzyme, 0.25 ⁇ Ci [ ⁇ - 33 P]ATP, assay buffer: 20 mM HEPES (pH 7.5), 0.15 M NaCI, 3mM MgCl 2 , 3mM MnCl 2 , 0.01% Triton X- 100, 1 mM DTT, 5% glycerol and 0.01% ⁇ -globulin.
  • the plate is incubated at room temperature (RT) for 60 minutes for the kinase reaction.
  • the reaction is stopped with 20 ⁇ l of 50mM EDTA and the biotinylated anti-MBP is allowed to bind to the HK and the Streptavidin for a further 60 minutes at RT.
  • the unbound reagents are washed away with 2 x 100 ⁇ l phosphate-buffered saline (PBS). Radioactivity is measured for 45 sec/well.
  • PBS phosphate-buffered sa

Abstract

Cette invention concerne des thiénopyrazoles, leur préparation, des compositions pharmaceutiques comprenant ces composés, ainsi que leurs utilisations pharmaceutiques dans le traitement d'états pathologiques, lesquels thiénopyrazoles peuvent être modulés par l'inhibition des protéines kinases, en particulier de la tyrosine kinase inductible par l'interleukine-2 (ITK).
PCT/US2004/023814 2003-09-08 2004-07-23 Thienopyrazoles WO2005026175A1 (fr)

Priority Applications (21)

Application Number Priority Date Filing Date Title
NZ545421A NZ545421A (en) 2003-09-08 2004-07-23 Thienopyrazoles
DK04779049.8T DK1682553T3 (da) 2003-09-08 2004-07-23 Thienopyrazoler
DE602004027288T DE602004027288D1 (en) 2003-09-08 2004-07-23 Thienopyrazole
AU2004272507A AU2004272507B2 (en) 2003-09-08 2004-07-23 Thienopyrazoles
SI200431462T SI1682553T1 (sl) 2003-09-08 2004-07-23 Tienopirazoli
YUP-2006/0162A RS20060162A (en) 2003-09-08 2004-07-23 Thienopyrazoles
EP04779049A EP1682553B1 (fr) 2003-09-08 2004-07-23 Thienopyrazoles
CA2538032A CA2538032C (fr) 2003-09-08 2004-07-23 Thienopyrazoles
AT04779049T ATE468341T1 (de) 2003-09-08 2004-07-23 Thienopyrazole
MXPA06001827A MXPA06001827A (es) 2003-09-08 2004-07-23 Tienopirazoles.
JP2006525328A JP4879739B2 (ja) 2003-09-08 2004-07-23 チエノピラゾール
PL04779049T PL1682553T3 (pl) 2003-09-08 2004-07-23 Tienopirazole
MEP-209/08A MEP20908A (en) 2003-09-08 2004-07-23 Thienopyrazoles
BRPI0414215-2A BRPI0414215A (pt) 2003-09-08 2004-07-23 tienopirazóis
TNP2006000058A TNSN06058A1 (en) 2003-09-08 2006-02-15 Thienopyrazoles
IL173916A IL173916A (en) 2003-09-08 2006-02-23 Thienopyrazole compound and a pharmaceutical product comprising the same
US11/368,566 US7518000B2 (en) 2003-09-08 2006-03-06 Thienopyrazoles
NO20061626A NO20061626L (no) 2003-09-08 2006-04-10 Tienopyrazoler
HK07100592A HK1095587A1 (en) 2003-09-08 2007-01-17 Thienopyrazoles
US12/411,818 US7928231B2 (en) 2003-09-08 2009-03-26 Thienopyrazoles
HR20100398T HRP20100398T1 (hr) 2003-09-08 2010-07-20 Tienopirazoli

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50115903P 2003-09-08 2003-09-08
US60/501,159 2003-09-08

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/368,566 Continuation US7518000B2 (en) 2003-09-08 2006-03-06 Thienopyrazoles

Publications (1)

Publication Number Publication Date
WO2005026175A1 true WO2005026175A1 (fr) 2005-03-24

Family

ID=34312256

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/023814 WO2005026175A1 (fr) 2003-09-08 2004-07-23 Thienopyrazoles

Country Status (30)

Country Link
US (2) US7518000B2 (fr)
JP (1) JP4879739B2 (fr)
KR (1) KR20060069490A (fr)
CN (1) CN100398545C (fr)
AT (1) ATE468341T1 (fr)
AU (1) AU2004272507B2 (fr)
BR (1) BRPI0414215A (fr)
CA (1) CA2538032C (fr)
CR (1) CR8255A (fr)
DE (1) DE602004027288D1 (fr)
DK (1) DK1682553T3 (fr)
EC (1) ECSP066411A (fr)
ES (1) ES2345257T3 (fr)
HK (1) HK1095587A1 (fr)
HR (1) HRP20100398T1 (fr)
IL (1) IL173916A (fr)
MA (1) MA28038A1 (fr)
ME (1) MEP20908A (fr)
MX (1) MXPA06001827A (fr)
MY (1) MY144339A (fr)
NO (1) NO20061626L (fr)
NZ (1) NZ545421A (fr)
OA (1) OA13252A (fr)
PT (1) PT1682553E (fr)
RS (2) RS51846B (fr)
RU (1) RU2358978C2 (fr)
TN (1) TNSN06058A1 (fr)
TW (1) TWI352705B (fr)
WO (1) WO2005026175A1 (fr)
ZA (1) ZA200601947B (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006101454A1 (fr) * 2005-03-21 2006-09-28 S*Bio Pte Ltd Derives du benzothiophene: preparation et applications pharmaceutiques
WO2007076228A2 (fr) * 2005-12-20 2007-07-05 Boehringer Ingelheim International Gmbh Inhibiteurs de kinases tec
EP2151433A1 (fr) 2008-08-05 2010-02-10 Institut Pasteur Alkoxypyrazoles et leur procédé de préparation
EP2151434A1 (fr) 2008-08-05 2010-02-10 Institut Pasteur Alkoxypyrazoles et leur procédé de préparation
US8299070B2 (en) 2009-11-25 2012-10-30 Japan Tobacco Inc. Indole compounds and pharmaceutical use thereof
WO2013092463A1 (fr) * 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag Inhibiteurs 4-azaindole du crac
WO2013153539A1 (fr) 2012-04-13 2013-10-17 Glenmark Pharmaceuticals S.A. Composés tricycliques à titre d'inhibiteurs de kinases tec
CN103467481A (zh) * 2012-06-07 2013-12-25 上海汇伦生命科技有限公司 二氢吡啶类化合物、其组合物、制备方法和用途
WO2014041518A1 (fr) * 2012-09-14 2014-03-20 Glenmark Pharmaceuticals S.A. Composés thiénopyrrole comme inhibiteurs de l'itk
WO2014081166A1 (fr) * 2012-11-21 2014-05-30 주식회사 두산 Composé organique et dispositif électroluminescent organique l'utilisant
US8835420B2 (en) 2012-07-10 2014-09-16 Takeda Pharmaceutical Company Limited Azaindole derivatives
US9371321B2 (en) 2014-01-09 2016-06-21 Astrazeneca Ab Azaindole derivatives
WO2017040617A1 (fr) 2015-08-31 2017-03-09 Pharmacyclics Llc Combinaisons d'inhibiteurs de btk pour le traitement du myélome multiple
WO2018085731A2 (fr) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Polythérapie de type thérapie cellulaire t et inhibiteur de btk
WO2019213184A1 (fr) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Polythérapie d'une thérapie par lymphocytes t à récepteur antigénique chimérique (car) et d'un inhibiteur de btk
EP4115886A1 (fr) 2013-10-25 2023-01-11 Pharmacyclics LLC Procédés de traitement et de prévention de la maladie du greffon contre l'hôte
WO2023139248A1 (fr) * 2022-01-21 2023-07-27 Ecole Polytechnique Federale De Lausanne (Epfl) Inhibiteurs de thioestérases de protéine acyle contre des infections microbiennes
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103720694A (zh) * 2012-10-11 2014-04-16 韩冰 一类治疗脑性瘫痪的化合物及其用途
CN103772391A (zh) * 2012-10-23 2014-05-07 杨子娇 一类治疗房角狭窄的化合物及其用途
WO2016010108A1 (fr) * 2014-07-18 2016-01-21 塩野義製薬株式会社 Dérivés hétérocycliques contenant de l'azote et compositions médicinales le contenant

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001053268A2 (fr) * 2000-01-18 2001-07-26 Agouron Pharmaceuticals, Inc. Composes d'indazole, compositions pharmaceutiques, et methodes destines a la mediation ou a l'inhibition de la proliferation cellulaire
US6358978B1 (en) * 1999-06-23 2002-03-19 Aventis Pharma Deutschland Gmbh Substituted benzimidazoles
US6462036B1 (en) * 1998-11-06 2002-10-08 Basf Aktiengesellschaft Tricyclic pyrazole derivatives
WO2003024969A1 (fr) * 2001-09-14 2003-03-27 Merck & Co., Inc. Inhibiteurs des tyrosine kinases
WO2003035644A1 (fr) * 2001-10-26 2003-05-01 Aventis Pharma S.A. Derives de benzimidazoles et_leur utilisation comme inhibiteurs de proteine kinase kdr

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297238B1 (en) * 1999-04-06 2001-10-02 Basf Aktiengesellschaft Therapeutic agents
BR0213562A (pt) * 2001-10-26 2004-08-31 Aventis Pharma Inc Benzimidazóis e análogos e seu uso como inibidores de cinases de proteìna

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6462036B1 (en) * 1998-11-06 2002-10-08 Basf Aktiengesellschaft Tricyclic pyrazole derivatives
US6358978B1 (en) * 1999-06-23 2002-03-19 Aventis Pharma Deutschland Gmbh Substituted benzimidazoles
WO2001053268A2 (fr) * 2000-01-18 2001-07-26 Agouron Pharmaceuticals, Inc. Composes d'indazole, compositions pharmaceutiques, et methodes destines a la mediation ou a l'inhibition de la proliferation cellulaire
WO2003024969A1 (fr) * 2001-09-14 2003-03-27 Merck & Co., Inc. Inhibiteurs des tyrosine kinases
WO2003035644A1 (fr) * 2001-10-26 2003-05-01 Aventis Pharma S.A. Derives de benzimidazoles et_leur utilisation comme inhibiteurs de proteine kinase kdr

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006101454A1 (fr) * 2005-03-21 2006-09-28 S*Bio Pte Ltd Derives du benzothiophene: preparation et applications pharmaceutiques
WO2007076228A2 (fr) * 2005-12-20 2007-07-05 Boehringer Ingelheim International Gmbh Inhibiteurs de kinases tec
WO2007076228A3 (fr) * 2005-12-20 2007-08-30 Boehringer Ingelheim Int Inhibiteurs de kinases tec
EP2151433A1 (fr) 2008-08-05 2010-02-10 Institut Pasteur Alkoxypyrazoles et leur procédé de préparation
EP2151434A1 (fr) 2008-08-05 2010-02-10 Institut Pasteur Alkoxypyrazoles et leur procédé de préparation
US8299070B2 (en) 2009-11-25 2012-10-30 Japan Tobacco Inc. Indole compounds and pharmaceutical use thereof
WO2013092463A1 (fr) * 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag Inhibiteurs 4-azaindole du crac
WO2013153539A1 (fr) 2012-04-13 2013-10-17 Glenmark Pharmaceuticals S.A. Composés tricycliques à titre d'inhibiteurs de kinases tec
CN103467481A (zh) * 2012-06-07 2013-12-25 上海汇伦生命科技有限公司 二氢吡啶类化合物、其组合物、制备方法和用途
US8835420B2 (en) 2012-07-10 2014-09-16 Takeda Pharmaceutical Company Limited Azaindole derivatives
WO2014041518A1 (fr) * 2012-09-14 2014-03-20 Glenmark Pharmaceuticals S.A. Composés thiénopyrrole comme inhibiteurs de l'itk
WO2014081166A1 (fr) * 2012-11-21 2014-05-30 주식회사 두산 Composé organique et dispositif électroluminescent organique l'utilisant
EP4115886A1 (fr) 2013-10-25 2023-01-11 Pharmacyclics LLC Procédés de traitement et de prévention de la maladie du greffon contre l'hôte
US9371321B2 (en) 2014-01-09 2016-06-21 Astrazeneca Ab Azaindole derivatives
WO2017040617A1 (fr) 2015-08-31 2017-03-09 Pharmacyclics Llc Combinaisons d'inhibiteurs de btk pour le traitement du myélome multiple
WO2018085731A2 (fr) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Polythérapie de type thérapie cellulaire t et inhibiteur de btk
WO2019213184A1 (fr) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Polythérapie d'une thérapie par lymphocytes t à récepteur antigénique chimérique (car) et d'un inhibiteur de btk
WO2023139248A1 (fr) * 2022-01-21 2023-07-27 Ecole Polytechnique Federale De Lausanne (Epfl) Inhibiteurs de thioestérases de protéine acyle contre des infections microbiennes
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t

Also Published As

Publication number Publication date
US20070254937A1 (en) 2007-11-01
US7518000B2 (en) 2009-04-14
TW200519118A (en) 2005-06-16
OA13252A (en) 2007-01-31
CA2538032A1 (fr) 2005-03-24
ECSP066411A (es) 2006-09-18
ZA200601947B (en) 2007-05-30
JP2007505038A (ja) 2007-03-08
HK1095587A1 (en) 2007-05-11
NZ545421A (en) 2010-03-26
ES2345257T3 (es) 2010-09-20
HRP20100398T1 (hr) 2010-09-30
TNSN06058A1 (en) 2007-10-03
US20100056514A1 (en) 2010-03-04
JP4879739B2 (ja) 2012-02-22
BRPI0414215A (pt) 2006-11-07
US7928231B2 (en) 2011-04-19
IL173916A (en) 2011-07-31
AU2004272507A1 (en) 2005-03-24
DK1682553T3 (da) 2010-08-23
IL173916A0 (en) 2006-07-05
CR8255A (es) 2006-07-14
CA2538032C (fr) 2011-01-11
DE602004027288D1 (en) 2010-07-01
AU2004272507B2 (en) 2011-05-12
RU2358978C2 (ru) 2009-06-20
RS20060162A (en) 2008-06-05
TWI352705B (en) 2011-11-21
NO20061626L (no) 2006-04-10
MY144339A (en) 2011-08-29
ATE468341T1 (de) 2010-06-15
MA28038A1 (fr) 2006-07-03
CN1849322A (zh) 2006-10-18
CN100398545C (zh) 2008-07-02
RS51846B (en) 2012-02-29
RU2006111470A (ru) 2007-10-27
PT1682553E (pt) 2010-07-29
KR20060069490A (ko) 2006-06-21
MXPA06001827A (es) 2006-05-31
MEP20908A (en) 2010-06-10

Similar Documents

Publication Publication Date Title
US7928231B2 (en) Thienopyrazoles
RU2422449C2 (ru) Фармацевтические соединения
US20200069643A1 (en) Pyrrolopyrrole compositions as pyruvate kinase (pkr) activators
JP6896715B2 (ja) セピアプテリン還元酵素としてのヘテロアリール誘導体
US7557114B2 (en) Heterocyclic-substituted phenyl methanones
US7745641B2 (en) Nitrogen-containing heterocyclic compound
KR100883003B1 (ko) 알츠하이머병의 치료를 위한 글라이신 수송체1(ｇｌｙｔ-1) 억제제로서 바이- 및 트라이사이클릭 치환된페닐 메탄온
EP0384349B1 (fr) Pyrroles substitués
TWI576346B (zh) 雙環吡嗪酮衍生物
SK280899B6 (sk) Použitie piperidínových derivátov, piperidínový derivát a farmaceutický prostriedok
KR20080009200A (ko) 치환된 헤테로사이클 및 이것의 ｃｈｋ1, ｐｄｋ1 및ｐａｋ 억제제로서의 용도
WO2009105500A1 (fr) Composés inhibiteurs de la voie erk
KR20180100227A (ko) 퀴놀린-2-온 유도체
MXPA04008671A (es) Derivados de pirrol-2,5-diona y su uso como inhibidores de gsk-3.
US7491729B2 (en) 3-Substituted 3,4-dihydro-thieno[2,3-d]pyrimidin-4-one derivatives, production and use thereof
AU2005229452A1 (en) Novel pyrrolo (2,3-b)pyridine derivatives, the preparation and the pharmaceutical use thereof in the form of kinase inhibitors
US20060235013A1 (en) Tricyclic azole derivatives
EP1682553B1 (fr) Thienopyrazoles
KR100519831B1 (ko) 티에노피롤리디논

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200480025742.4

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BW BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE EG ES FI GB GD GE GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MK MN MW MX MZ NA NI NO NZ PG PH PL PT RO RU SC SD SE SG SK SY TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SZ TZ UG ZM ZW AM AZ BY KG MD RU TJ TM AT BE BG CH CY DE DK EE ES FI FR GB GR HU IE IT MC NL PL PT RO SE SI SK TR BF CF CG CI CM GA GN GQ GW ML MR SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: PA/a/2006/001827

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 545421

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 12006500387

Country of ref document: PH

Ref document number: 173916

Country of ref document: IL

Ref document number: CR2006-008255

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: DZP2004000111

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 11368566

Country of ref document: US

Ref document number: 2538032

Country of ref document: CA

Ref document number: 794/CHENP/2006

Country of ref document: IN

Ref document number: P-2006/0162

Country of ref document: YU

WWE Wipo information: entry into national phase

Ref document number: 2006/01947

Country of ref document: ZA

Ref document number: KE

Ref document number: 06022831

Country of ref document: CO

Ref document number: 2004272507

Country of ref document: AU

Ref document number: 2006525328

Country of ref document: JP

Ref document number: 200601947

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 1020067004795

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2004779049

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2004272507

Country of ref document: AU

Date of ref document: 20040723

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004272507

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2006111470

Country of ref document: RU

Ref document number: 1200600566

Country of ref document: VN

WWP Wipo information: published in national office

Ref document number: 1020067004795

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2004779049

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0414215

Country of ref document: BR

WWP Wipo information: published in national office

Ref document number: 11368566

Country of ref document: US